Diseases Of Immunity

DISEASES OF IMMUNITY ROBERTO D. PADUA JR., MD, DPSP DEPARTMENT OF PATHOLOGY FATIMA COLLEGE OF MEDICINE

The immune system protects the host from invasion by foreign and potentially harmful agents. Characteristics: 1. distinguish self from non-self 2. discriminate among potential invaders (specificity) 3. maintain the presence of immune memory (anamnesis) 4. recall previous exposures and mount an amplified response to them

☻ Immune responses can be elicited by a wide range of agents (termed antigens ) including microorganisms, chemicals, toxins, drugs, and transplanted tissues ☻ Adaptive immunity – immune responses that show antigen specificity and immune memory ☻ Innate immunity – does not demonstrate immune memory and lacks the exacting specificity of adaptive immunity

Mechanisms involved in Innate and Adaptive immunity

Innate and Adaptive Immunity Innate Immunity Natural or native immunity Defense mechanisms present even before infection First line of defense Components Epithelial barriers Phagocytic cells (PMN’s and Macrophages) Dendritic cells NK cells Several plasma proteins, including the Complement system

Innate and Adaptive Immunity Innate Immunity Two most important cellular reactions 1. Inflammation  phagocytic leukocytes are recruited and activated to kill microbes 2. Anti-viral defense  mediated by dendritic cells and NK cells

Innate and Adaptive Immunity Innate Immunity  Pathogen-associated molecular patterns * Microbial structures recognized by leukocytes and epithelial cells  Danger-associated molecular patterns * Molecules released by injured and necrotic cells that are recognized by leukocytes *Pattern recognition receptors  Toll-like receptors (TLR’s)

Innate and Adaptive Immunity Toll-like Receptors (TLR’s)  homologous to the Drosophila protein  specific for components of different bacteria and viruses  located on the cell surface and in endosomes *Recognize and initiate cellular responses

Different TLRs involved in response to different microbial products

Innate Immunity Epithelia (skin, respiratory, GIT)  provide mechanical barriers to the entry of microbes  produce anti-microbial molecules = defensins

Innate Immunity Monocytes and Neutrophils  phagocytes in the blood recruited at the site of infection  monocytes that enter the tissues and mature are called macrophages

Innate Immunity Dendritic cells  produce type I interferons, anti-viral cytokines that inhibit viral infection and replication Natural killer cells  provide early protection against many viruses and intracellular bacteria

Innate Immunity Complement proteins * activated by binding to microbes using the alternative and lectin pathways

Innate Immunity Mannose-binding lectin and C-reactive protein * coat microbes for phagocytosis and complement activation Lung surfactant * protection against inhaled microbes

Adaptive Immunity consists of lymphocytes and their products, including antibodies

Adaptive Immunity Cell-mediated (cellular) immunity  responsible for defense against intracellular microbes  mediated by T (Thymus-derived) lymphocytes Humoral immunity  protects against extracellular microbes and their toxins  mediated by B (Bone-marrow derived) lymphocytes and their secreted products  antibodies

CELLS OF THE IMMUNE SYSTEM Present Ag to CD4 T cells Precursors to macrophage lineage; cytokine release Class II MHC expressing cells Horse-shoe shaped nucleus Found in LN, blood, lungs and other organs Antigen Presenting Cells Monocytes Phagocytose and kill bacteria Parasitic defense and allergic response ___ None Staining with eosin ___ Granulocyte; short lifespan; multilobed nucleus Bilobed nucleus; heavily granulated cytoplasm See below Phagocytic cells: PMN’s Eosinophils Macrophages Kill antibody-decorated cells and virus-infected or tumor cells (no MHC restriction) Fc receptors for antibody: CD16, CD56, CD57 Large granular lymphocytes Natural Cytolytic cells: NK cells FUNCTION MARKERS CHARACTERISTICS CELLS

CELLS OF THE IMMUNE SYSTEM Initiate inflammatory and acute phase response; have antibacterial, antiviral and anti-tumor activities Transport Ag to LN Efficient Ag presenters Produce cytokines Filter particles from blood Large, granular cells; Fc and C3 receptors __ __ __ __ __ Possible residence in tissue, spleen, LN, and other organs; activated by IFN- γ and TNF Presence in skin LN, tissues CNS and brain Presence in liver See below Antigen Presenting Cells Macrophages Langerhan’s cells Dendritic cells Microglial cells Kupffer cells B cells FUNCTION MARKERS CHARACTERISTICS CELLS

CELLS OF THE IMMUNE SYSTEM Produce IL-2, other cytokines; stimulate T-cell and B-cell growth; promote B-cell differentiation, antibody production Promotes initial defenses (local) DTH, T killer cells Promote later humoral responses CD2, CD3, T-cell receptor CD2, CD3, T-cell receptor, CD4 IL-2, IFN- γ , lympho-toxin production IL-4, IL-5, IL-6, IL-10 production Mature in Thymus; large nucleus, small cytoplasm Helper/DTH cells; Activation by APCs via Class II MHC antigen presentation TH 1 subtype TH 2 subtype Antigen-Responsive Cells T cells (all) CD4 T cells FUNCTION MARKERS CHARACTERISTICS CELLS

CELLS OF THE IMMUNE SYSTEM Release Histamine, provide allergic response, anti-parasitic Fc receptor for IgE Granulocytic Other cells Basophils/Mast cells Produce antibody and present antigen Terminally differentiated, antibody factories Surface antibody, Class II MHC antigens __ Mature in Peyer’s patches, BM, bursal equivalent; large nucleus, small cytoplasm; activation by Ag and T-cell factors Small nucleus, large cytoplasm Antibody-, Producing Cells B cells Plasma cells Kill viral, tumor, non-self cells; secrete TH 1 lymphokines Suppress T- cell and B-cell response CD2, CD3, T-cell receptor, CD8 CD2, CD3, T-cell receptor, CD8 Recognition of Ag presented by Class I MHC antigens Recognition of Ag presented by Class I MHC antigens Antigen-Responsive Cells CD8 T killer cells CD8 T cells (suppressor cells ) FUNCTION MARKERS CHARACTERISTICS CELLS

T Lymphocytes Generated from immature precursors in the thymus Mature, naïve T cells enters the circulation, constituting 60-70% of lymphocytes Found in the paracortical areas of LN and periarteriolar sheaths of spleen Each T cell is genetically programmed to recognize a specific cell-bound antigen by means of an antigen-specific T cell receptor (TCR)

B lymphocytes Develop from immature precursors in the bone marrow Mature B cells constitute 10-20% of the circulating peripheral lymphocytes Also seen in the LN (superficial cortex), spleen (white pulp), tonsils, and extralymphatic organs (e.g. GIT) Recognizes antigen via the B-cell antigen receptor complex Has unique antigen specificity derived partly from somatic rearrangements of immunoglobulin gene

Cytokines ☻ Short-acting soluble mediators ☻ Includes lymphokines, monokines and other polypeptides that regulate immunologic, inflammatory, and reparative host responses ☻ Molecularly defined cytokines - Interleukins

Cytokines Mediate innate (natural) immunity ♣ IL-1, TNF, type 1 IFN, IL-6 ♣ IL-12 and IFN- γ (innate and adaptive immunity) Regulate lymphocyte growth, activation and differentiation ♣ IL-2, IL-4, IL-12, IL-15 and TGF-B

Cytokines 3. Activate inflammatory cells ♣ IFN- γ – macrophages ♣ IL-5 – eosinophils ♣ TNF and TNF- Β – PMN’s and endothelial cells 4. Affect leukocyte movement (Chemokines) ♣ C-C and C-X-C chemokines 5. Stimulate hematopoiesis ♣ derived from lymphocytes or stromal cells ♣ colony-stimulating factors

Cytokines General Properties ☺ produced by different cell types ☺ pleiotropic actions ☺ induce effects in 3 ways 1. act on the same cell that produces them (autocrine effect) 2. affect other cells in the vicinity (paracrine effect) 3. affect many cells systematically (endocrine effect) ☺ mediate their effects by binding to specific high- affinity receptors on their target cells

SUBSETS OF T HELPER CELLS IN RESPONSE TO STIMULI (MAINLY CYTOKINES)

Histocompatibility Molecules ☼ Important for the induction and regulation of the immune response ☼ Principal physiologic function is to bind peptide fragments of foreign proteins for presentation to antigen-specific T cells ☼ Encoding genes are found in chromosome 6 MHC or HLA complex ☼ Class I and Class II genes encode cell surface glycoproteins involved in antigen presentation ☼ Class III genes encode components of the complement system

Histocompatibility Molecules Categories: 1. Class I MHC molecules ► expressed on all nucleated cells and platelets ► encoded by 3 closely linked loci – HLA-A, Hla-B, and HLA-C ► heterodimer molecules – polymorphic α linked noncovalently to nonpolymorphic peptide β -2 microglobulin ► CD8 T cells

Histocompatibility Molecules Categories: 2. Class II MHC molecules ► coded in the HLA-D region (HLA-DP, HLA-DQ, and HLA-DR) ► heterodimer, noncovalently binded α and β chains ► CD4 T cells

Histocompatibility Molecules HLA and Disease Association ► mechanisms not fully understood ► grouped into the following categories ◘ Inflammatory diseases ◘ Inherited errors of metabolism ◘ Autoimmune disorders

HLA and Disease Association 15.0 BW47 21-Hydroxylase deficiency 5 6 20 DR3 DR4 DR3/DR4 Type I diabetes 9 DR3 Primary Sjogren syndrome 13 DR3 Chronic active hepatitis 4 DR4 Rheumatoid arthritis 14 B27 Acute anterior uveitis 14 B27 Post-gonococcal arthritis 90 B27 Ankylosing spondylitis Relative Risk HLA Allele Disease

Disorders of the Immune System ╬ Hypersensitivity reactions ╬ Autoimmune diseases ╬ Immunologic deficiency syndromes ╬ Amyloidosis

Hypersensitivity Reactions and Tissue injury ۩ Hypersensitivity is a misnomer ۩ These diseases result from normal immune responses ۩ Not Excessive or ‘Hyper’ responses ۩ Classification based on Immunologic Mechanisms

General features of hypersensitivity disorders Both exogenous and endogenous antigens may elicit hypersensitivity reactions The development of hypersensitivity diseases (both allergic and autoimmune disorders) is often associated with the inheritance of particular susceptibility genes Hypersensitivity reflects an imbalance between the effector mechanisms of immune responses and the control mechanisms that serve to normally limit such responses

۩ Results in tissue injury or other pathophysiological changes ۩ Occurs when an already sensitized individual is re- exposed to the same foreign substance ۩ May be immediate or delayed Hypersensitivity Reactions and Tissue Injury

Ensuing tissue injury may be caused by: ۩ Release of vasoactive substances ۩ Phagocytosis or lysis of cells ۩ Activation of inflammatory & cytolytic components of complement system ۩ Release of cytokines, proteolytic enzymes and other mediators of tissue injury or inflammation Hypersensitivity Reactions and Tissue Injury

Immediate (Type I) Hypersensitivity A rapidly developing immunologic reaction occurring within minutes after the combination of an antigen with antibody bound to mast cells in individuals previously sensitized to the antigen The reaction is called an allergy, and the antigen that cause them are termed allergen Most are mediated by IgE antibody-dependent activation of mast cells and other leukocytes

Immediate (Type I) Hypersensitivity Anaphylactic type Occurs within minutes IgE mediated Provoked by re-exposure to the same antigen (by contact, inhalation, ingestion, or injection) Mediated by antigen binding with antibody previously bound to mast cells or basophils Local or systemic

Immediate (Type I) Hypersensitivity LOCAL ANAPHYLAXIS ♠ Atopy  genetically determined predisposition to develop localized anaphylactic reactions to inhaled or ingested allergens ♠ positive family history  chromosome 5q31 ♠ With higher serum IgE levels compared to general population

Immediate (Type I) Hypersensitivity Two Phase Reaction ♠ Initial response is rapid - 5-30 min after exposure to antigen (subsides in 60 minutes) ◘ Vasodilatation, edema, smooth muscle spasm ♠ Late phase response - 2-8 hrs later ◘ Occurs in 50% of patients ◘ Infiltration by monocytes, eosinophils, basophils, PMN’s and CD4 T cells ◘ With mucosal epithelial damage

Kinetics of the immediate and late-phase reactions

Type I Hypersensitivity ♠ Mast cells in tissues; Basophils circulate ♠ Both contain granules with Inflammatory Mediators ♠ Activated by cross-linking to IgE Fc receptors

Vasodilatation, increased vascular permeability Smooth muscle spasm Cellular infiltration

Immediate (Type I) Hypersensitivity Primary Mediators ♠ Preformed and stored in granules ♠ Histamine ♠ Chemotactic factors for eosinophils and PMN’s ♠ Proteases

Immediate (Type I) Hypersensitivity Secondary Mediators ♠ Lipid Mediators ◘ Platelet Activating Factor ◘ Arachidonic Acid ☻ Leukotrienes and Prostaglandin ♠ Cytokines ◘ TNF-alpha ◘ Interleukins 1, 4, 5, 6

Immediate (Type I) Hypersensitivity ۞ Is the result of release of ‘a variety of chemotactic, vasoactive and spasmogenic compounds’

Immediate (Type I) Hypersensitivity CLINICAL MANIFESTATIONS ♠ Systemic Disorder ♠ Local Reaction

Immediate (Type I) Hypersensitivity SYSTEMIC ANAPHYLAXIS ♠ characterized by vascular shock, widespread edema, and difficulty in breathing ♠ Hospital setting = Antisera, hormones, enzymes, polysaccharides, and drugs (penicillin) ♠ Community setting = food allergies, insect toxins ♠ Itching, hives, skin erythema within minutes  respiratory difficulty or GIT symptoms ♠ Shock and Death can occur within minutes

Immediate (Type I) Hypersensitivity LOCAL REACTIONS ♠ A ffects 10-20% of the population ♠ Skin or Mucosal Surfaces ◘ Urticaria (Hives) ♠ Skin and food allergies ♠ Hay fever ♠ Atopy - familial predisposition to allergy

Immediate (Type I) Hypersensitivity What good is it? ☻ Fights Worm infection ☻ EEEEWWWWWW!!!!

What is Asthma? ♠ Hypersensitivity – Allergy , Type I ♠ Affects airways of lungs - Bronchi ♠ Allergens – in the air, mast cell - IgE ab. ♠ Inflammation of airways – Bronchitis. ♠ Genetic, Environmental, Race, Age. ♠ High in industrial cities 4-19%, Fiji < 1% ♠ Increasing incidence …!

Asthma Mechanism: ► Allergy ► Inflammation of bronchi ► Obstruction ► Mucous Plugs

INFLAMMATION Airflow Limitation TRIGGERS Exercise Cold Air, diseases, Airway Hyperresponsiveness Genetic* INDUCERS Allergens,pollutants

Lung in Asthma with Mucous plugs

Asthma Microscopic Pathology Obstructed and inflamed bronchi

Asthma - Bronchial morphology ◘ Inflammation ◘ Eosinophils ◘ Gland hyperplasia ◘ Mucous plug in lumen ◘ Hypertrophy of muscle layer

IgE and parasites: IgE binds to parasite, then Eosinophil binds Degranulation!

Type I Hypersensitivity DIAGNOSIS: ♠ History ♠ Skin prick test – (+) wheal & flare ♠ CBC showing eosinophilia ♠ RAST (Radioallergosorbent assay)

Type I Hypersensitivity TREATMENT: ♠ Anti-histamine – acts on first phase only ♠ Corticosteroids – late phase reaction ♠ Desensitization – to induce tolerance; no IgE production  deplete already bound IgE

Antibody-Mediated (Type II) Hypersensitivity ♥ Mediated by antibodies directed toward antigens present on the cell surfaces or extracellular matrix ♥ IgG and IgM ♥ Antigenic determinants – intrinsic or exogenous

Antibody-Mediated (Type II) Hypersensitivity MECHANISMS: ♥ Opsonization and Complement-and Fc Receptor-Mediated Phagocytosis  Cells targeted by antibodies are coated (opsonized) with molecules that make them attractive for phagocytes  Activates the complement system producing C3b and C4b  deposited on the surface of the cells and recognized by phagocytes (Fc receptors)  Results to the phagocytosis of the opsonized cells and their destruction  Complement activation  formation of MAC  disrupts membrane integrity  osmotic lysis of cells

Type II Hypersensitivity Reaction – Opsonization and Complement-and Fc-Receptor Mediated Phagocytosis

Antibody-Mediated (Type II) Hypersensitivity *Antibody-dependent cellular cytotoxicity (ADCC)  does not involve fixation of complement, requires cooperation of leukocytes  Coated cells with low concentrations of IgG antibody are killed by a variety of effector cells (monocytes, PMNs, eosinophils, and NK cells)  bind to the target by their receptors to the Fc fragment of IgG  cell lysis without phagocytosis

MECHANISMS: Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) Source: Robbins PATHOLOGIC BASIS OF DISEASE 6 th ed.

Antibody-Mediated (Type II) Hypersensitivity Clinical Conditions 1. Transfusion reaction - cells from an incompatible donor react with and are opsonized by preformed antibody in the host 2. Erythroblastosis fetalis - there is an antigenic difference b/w the mother and the fetus, and antibodies (IgG) from the mother cross the placenta and cause destruction of RBCs 3. Autoimmune hemolytic anemia, agranulocytosis, thrombocytopenia - individuals produce antibodies to their own blood cells which are then destroyed 4. Certain drug reactions - antibodies are produced that reacts with the drug, which may be attached to the surface of RBCs or other cells

An example of type II hypersensitivity

Pathogenic functions of auto-antibodies ------------------------------------------------------------ type II hypersensitivity response - ex: RBC autoantibodies ==> hemolysis ------------------------------------------------------------ C’

Antibody-Mediated (Type II) Hypersensitivity ♥ Complement-and Fc Receptor-Mediated Inflammation  antibodies deposited in extracellular tissues (basement membrane and matrix  activate complement (C5a, C4a, and C3a)  recruits PMNs and monocytes  release injurious substances (enzymes and reactive O2 intermediates  inflammation

Antibody-Mediated (Type II) Hypersensitivity – Complement-and Fc Receptor-Mediated Inflammation

Antibody-Mediated (Type II) Hypersensitivity ***Responsible for tissue injury in some form of glomerulonephritis, vascular rejection in organ grafts, and other diseases

Antibody-Mediated (Type II) Hypersensitivity ♥ Antibody-Mediated Cellular Dysfunction  Antibodies directed against cell-surface receptors impair or dysregulate function without causing cell injury or inflammation

Antibody-Mediated (Type II) Hypersensitivity – Antibody-Mediated Cellular Dysfunction

Pathogenic functions of auto-antibodies ------------------------------------------------------------ type II hypersensitivity response - ex: GBM autoantibodies ==> glomerulonephritis Goodpasture’s syndrome GBM Podocytes

Immune Complex-Mediated (Type III) Hypersensitivity ☻ Antigen-antibody complexes produce tissue damage mainly by eliciting inflammation at the sites of deposition

Immune Complex-Mediated (Type III) Hypersensitivity ♦ Antigen - Antibody Complexes initiate acute inflammation ◘ Complement activation and accumulation of PMN’s ♦ Endogenous Antigens – DNA ◘ circulating Ag’s present in the blood, or, more commonly, antigenic components of one’s own cells and tissues ♦ Exogenous Antigens - Bacteria, Viruses, Foreign protein, etc. ♦ Immune Complexes form in circulation or ♦ Antigens are ‘planted’ and IC’s form in situ ♦ Can be generalized or localized

Pathogenesis of immune-complex disease

Systemic Immune Complex Disease Prototype disorder – Acute serum sickness Frequent sequela to the administration of large amounts of foreign serum (e.g. horse immune serum for passive immunization) Pathogenesis (3 phases) 1. formation of Ag-Ab complexes 2. deposition of immune complexes 3. inflammatory reaction at the site of deposition

Systemic Immune Complex Disease Two mechanisms causing inflammation at the site of deposition 1. activation of the complement cascade 2. activation of neutrophils and macrophages through their Fc receptors  release of pro-inflammatory substances (prostaglandins, vasodilator peptides, chemotactic substances, lysosomal enzymes, oxygen free radicals)

Systemic Immune Complex Disease *** The important role of complement in the pathogenesis of the tissue injury is supported by the observations that during the active phase of the disease, consumption of complement decreases the serum levels, and experimental depletion of the complement greatly reduces the severity of the lesion.

Systemic Immune Complex Disease ***Chronic form of serum sickness results from repeated or prolonged exposure to an antigen ***Continous antigenemia is necessary for the development of chronic immune complex disease because complexes in antigen excess are the ones deposited in vascular beds – e.g. SLE

Systemic Immune Complex Disease Morphology  acute necrotizing vasculitis, with necrosis of vessel wall and intense neutrophilic infiltration  fibrinoid necrosis – smudgy, eosinophilic deposit that obscures the underlying cellular detail  affected glomeruli are hypercellular because of swelling and proliferation of endothelial and mesangial cells, accompanied by neutrophilic and monocytic infiltration  IF microscopy – granular lumpy deposits of Ig and Complement  Electron microscopy – electron-dense deposits along GBM

Systemic Immune Complex Disease ◘ Tissues affected ☼ Kidneys, joints, skin, heart, serosal surfaces and small vessels ◘ The reason(s) for this specific organ/tissue predeliction is unknown

Vasculitis Immune complex vasculitis. The necrotic vessel wall is replaced by smudgy, pink “fibrinoid” material.

Local Immune Complex Disease ♦ LOCAL (ARTHUS REACTION) ◘ Localized tissue necrosis from acute immune vasculitis ◘ Can induce experimentally by injecting antigen into the skin of a pre-sensitized recipient ◘ Local PMN recruitment and fibrinoid necrosis  thrombi formation  local ischemic injury

T Cell-Mediated (Type IV) Hypersensitivity ♣ T-Cells are the active agents not Antibodies ☼ Otherwise Type II is very similar to Type IV ♣ Delayed-Type  mediated by CD4+ T cells ♣ Direct Cell Cytotoxicity  mediated by CD8+ T cells

Mechanisms of Delayed Type Hypersensitivity Reactions

Mechanism of Direct T Cell Cytotoxicity

Type IV Hypersensitivity Delayed Type ♣ Tuberculin Skin Test (Mantoux Reaction) ♣ Granuloma Formation Nodular aggregate of Epithelioid Macrophages surrounded by a rim of lymphocytes Multinucleated Giant Cells may be present ♣ Persistent organisms that are poorly degraded (tuberculosis)

Type IV Hypersensitivity Delayed Type ♣ “ The Type of inflammation characteristic of this Reaction is called Granulomatous Inflammation” ♣ The key cell is the epithelioid macrophage NOT the Giant Cell!!

Formation of granuloma in Type IV Hypersensitivity

Granulomas Low Power High Power

Langhan’s Giant Cell Picture Robbins Textbook of Pathology 1971

Type IV - Cell Mediated Delayed Hypersensitivity ♣ TB antigen processing by macrophages  presentation to CD4 T cells  sensitized CD4 cells that remain in the circulation Re-exposure  activation, amplification and recruitment of Macrophages which cause the majority of tissue damage IL-2 and IFN-gamma are the most important cytokines

Type IV - Cell Mediated Delayed Type ♣ Major defense against Tuberculosis & Fungi

Type IV - Cell Mediated Delayed Type ♣ Major defense against Tuberculosis & Fungi ♣ Patients with AIDS have little defense against these organisms due to the extreme decline in CD4 cells

Type IV - T-cell Mediated Cytotoxicity ♣ Sensitized T cell directly kill cells ♣ Major role in Transplant Rejection ♣ Protects against Viral Infections

Type IV - T-cell Mediated Cytotoxicity ♣ CD8 or Cytotoxic T Lymphocytes are the effector cells ◘ Lyse target cells Perforin release leads to osmotic lysis Fas binding leads to apoptosis ◘ Release cytokines e.g. interferon gamma

Key Facts on Hypersensitivity Reactions Type I : IgE/mast cell-mediated liberation of histamine. Local and systemic anaphylaxis. Type II: antibodies bind to cell surface. Damage by complement activation or cellular cytotoxicity, or may stimulate/block a receptor Type III: antigen-antibody complexes, either local or circulating. Cause damage by activating complement in tissues at site of trapping of complexes. Type IV: T-cell mediated: CD4 cells recruit macrophages; CD8 cells cause cytotoxicity

Transplant Rejection Factors enhancing graft survival ABO blood group compatibility between recipients and donors Absence of pre-formed anti-HLA cytotoxic antibodies in recipients People must have previous exposure to blood products to develop HLA cytotoxic antibodies Close matches of HLA-A, -B, and –D loci between recipients and donors

Transplant Rejection Type of grafts Autograft (i.e., self to self) Associated with the best survival rate Syngenetic graft (isograft) Between identical twins Allograft Between genetically different individuals of the same species Xenograft Between two species Example = transplant of heart valve from pig to human

Transplant Rejection ◙ Involves recognition of major histocompatibility antigens (HLA) The most important HLA presenting cells are the donor lymphocytes, especially dendritic cells, contained within the graft Mediated by: CD8+ & CD4+ T cells

Transplant Rejection ◙ T cells Lyse graft cells Attract and activate macrophages Increase vascular permeability with local accumulation of lymphocytes and macrophages

Hyperacute Transplant Rejection ◙ Preformed anti-donor antibodies are present Hx of previous Transplant Multiparous women Previous blood transfusions ◙ Circulating antibodies react with the graft

Hyperacute Rejection Pathogenesis ABO incompatibility or action of preformed anti-HLA antibodies in the recipient directed against donor antigens in vascular endothelium Type II hypersensitivity reaction

Hyperacute Transplant Rejection ◙ Complement fixes, PMN’s arrive ◙ Graft destroyed in MINUTES to hours ◙ This no longer occurs Much better graft screening

Morphology of Rejection Hyper-acute Rejection ۩۩۩ Widespread arteritis, thrombosis of vessels, and ischemic necrosis

Microthrombi PMN’s Hyperacute Rejection

Antibody- mediated damage to the blood vessel in a renal allograft. The blood vessel is markedly thickened and the lumen is obstructed by proliferating fibroblast and foamy macrophages.

Acute Rejection Most common transplant rejection Reversible reaction that occurs within days to weeks 1) Type IV cell-mediated hypersensitivity CD4 T cells release cytokines, resulting in activation of host macrophages, proliferation of CD8 T cells  destruction of donor graft cell Extensive interstitial round cell lymphocytic infiltrate in the graft, edema, and endothelial cell injury

Acute Rejection 2) Antibody-mediated Type II hypersensitivity reaction - Cytokines from CD4 T cells promote B-cell differentiation into plasma cells  anti-HLA antibodies  attack vessels in the donor graft - Vasculitis with intravascular thrombosis in recent grafts - Intimal thickening with obliteration of vessel lumens in older grafts

Acute Rejection ***Acute rejection is potentially reversible with immunosuppressive agents such as cyclosporine (blocks CD4 T-cell release of IL-2), OKT3 (monoclonal antibody against T-cell antigen recognition site and corticosteroids (lymphotoxic) ***Immunosuppressive therapy is associated with an increased risk of cervical squamous cancer, malignant lymphoma, and skin squamous cell carcinoma (most common)

Morphology of Acute Rejection ۞ Onset usually 7-10 days ۞ Detected by slight rise in serum creatinine ۞ Mononuclear cell tubulo-interstitial infiltrate with tubular injury and interstitial edema ۞ Vasculitis is very uncommon

Acute cellular rejection of a renal allograft R – Intense mononuclear cell infiltrate between the glomerulus and the tubules L – Tubules undergoing destruction by invading lymphocytes

Acute Tubulointerstitial Rejection

Acute Tubulointerstitial Rejection Tubulitis

Acute Vascular Rejection Vasculitis

Chronic Rejection ۞ Irreversible reactions that occurs over months to years ۞ Involves continued vascular injury with ischemia to tissues ۞ Dominant histological features arterial and arteriolar intimal thickening thick glomerular capillary walls tubular atrophy interstitial fibrosis ۞ Cause is unclear ۞ Therapy is ineffective

Schematic representation that lead to the destruction of histo-incompatible grafts

Transplantation of Other Solid Organs In heart and liver transplants, unlike kidney transplantation, no effort is made to match HLA antigens in donor and hosts This is due to size compatibility requirements & The time a liver/heart remains viable is low

Allogeneic Hematopoietic Cell Transplant Bone Marrow Transplants Graft - versus - host disease and transplant rejection can occur Rejection is mediated by T cells and NK cells

Bone Marrow Transplants Graft - Versus - Host Disease Causes Potential complication in bone marrow transplant Potential complication in blood transfusions given to patients with a T-cell immunodeficiency and newborns

Bone Marrow Transplants Graft - Versus - Host Disease Pathogenesis Donor T-cells recognize host tissue as foreign and activate host CD4 and CD8 T cells Clinical Findings Bile duct necrosis (jaundice) Gastrointestinal mucosa ulceration (bloody diarrhea) Dermatitis

Bone Marrow Transplants Graft - Versus - Host Disease Donor marrow cells recognize host as “Foreign” The host is “rejected” Three principal targets: Liver Skin GI tract

SOME TYPES OF TRANSPLANTS Graft contains pluripotential cells that repopulate host stem cells Host assumes donor ABO group Danger of graft-versus-host reaction and CMV infection Bone marrow Better survival with kidney from living donor than from cadaver Kidney Best allograft survival rate Danger of transmission of C-J disease Cornea COMMENTS TYPE OF TRANSPLANT

Introduction Autoimmunity- immune reaction against “self-antigens”  Tissue damage Single organ or multi-system diseases More than 1 auto-antibody in a given disease may occur Common in females

Autoimmunity Three Requirements 1. The presence of an immune reaction specific for some self-antigen or self-tissue 2. Evidence that such a reaction is not secondary to tissue damage but is of primary pathogenic significance 3. The absence of another well-defined cause of the disease

Autoimmunity Clinical manifestations Variable Organ-specific disease immune responses are directed against a single organ or tissue Systemic or generalized disease Autoimmune reactions are against widespread antigens *** Results from loss of self-tolerance

Immune-mediated Inflammatory Disease Diseases mediated by antibodies and immune complexes Organ-specific autoimmune diseases Autoimmune Hemolytic anemia Autoimmune thrombocytopenia Myastenia gravis Graves disease Goodpasture syndrome Systemic autoimmune diseases Systemic Lupus Erythematosus (SLE) Diseases caused by autoimmunity or by reactions to microbial antigens Polyarteritis nodosa

Immune-mediated Inflammatory Disease Diseases mediated by T cells Organ-specific autoimmune diseases Type I Diabetes mellitus Multiple sclerosis Systemic autoimmune diseases Rheumatoid arthritis* Systemic sclerosis* Sjogren syndrome* Diseases caused by autoimmunity or by reactions to microbial antigens Inflammatory bowel disease (Crohn disease, Ulcerative colitis) Inflammatory myopathies *Antibodies may also play a role in these diseases

Immunological Tolerance It is the phenomenon of unresponsiveness to an antigen as a result of exposure to lymphocytes to that antigen Self-tolerance  lack of responsiveness to an individual’s own antigen Underlies our ability to live in harmony with our cells and tissues Lymphocytes with receptors capable of recognizing self-antigens are being generated constantly  eliminated or inactivated as soon as they recognize the antigens Mechanisms : Central tolerance and Peripheral tolerance

CENTRAL TOLERANCE Negative selection or deletion of self-reactive T and B lymphocytes during their maturation in the central lymphoid organs T cells T lymphocytes that bear high-affinity receptors for self-antigens are negatively selected or deleted  undergo apoptosis AIRE (autoimmune regulator) – a protein that stimulates expression of some “peripheral tissue-restricted” self-antigens in thymus  critical for deletion of immature T cells specific for these antigens occur during fetal development

CENTRAL TOLERANCE B cells Also undergo negative selection or deletion Receptor Editing – when developing B cells strongly recognize self antigens in the BM  reactivate the machinery of antigen receptor gene rearrangement  express new antigen receptors not specific for self-antigens Failure  self-reactive cells undergo apoptosis  purging dangerous lymphocytes from the mature pool Occurs throughout life

PERIPHERAL TOLERANCE Self-reactive T cells that escape intra-thymic negative selection are deleted or muzzled in the peripheral tissues

PERIPHERAL TOLERANCE  Silence potentially autoreactive T and B cells in peripheral tissues  Best defined for T cells  Mechanisms: 1. Anergy 2. Suppression by regulatory T cells 3. Deletion by activation-induced cell death

PERIPHERAL TOLERANCE Anergy  Prolonged or irreversible functional inactivation of lymphocytes, induced by encounter with antigens  T cells – due to absence of co-stimulatory molecules on APCs, such as B7-1 & B7-2  B cells – due to lack of T cell help for antibody synthesis (T cell anergy or down-regulation of surface IgM)

PERIPHERAL TOLERANCE Suppression by regulatory T cells  Regulatory T cells plays a major role in preventing immune reactions against self-antigens  CD4 T cells is the best defined regulatory T cells that expresses CD25, the alpha chain of the IL-2 receptor, and a transcription factor of the forkhead family (Foxp3) ***both are required for the development and maintenance of functional CD4+ regulatory T cells  Mutations in Fox3p result in severe autoimmunity ***cause of autoimmune disease called IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked)

PERIPHERAL TOLERANCE Deletion by activation-induced cell death  CD4+ T cells that recognize self-antigens may receive signals that promote their death by apoptosis  two mechanisms 1. Expression of a pro-apoptotic member of the Bcl family (Bim), without anti-apoptotic members of the family, Bcl-2 and Bcl-x  unopposed Bim triggers apoptosis by the mitochondrial pathway 2. Involves the Fas-Fas ligand system  engagement of Fas by FasL induces apoptosis of activated T cells by the death receptor pathway

MECHANISMS OF IMMUNOLOGICAL TOLERANCE

MECHANISMS OF IMMUNOLOGICAL TOLERANCE. 7H EDITION

Mechanism of Autoimmunity Autoimmunity arises from a combination of the inheritance of susceptibility genes, which may contribute to the breakdown of self-tolerance, and environmental triggers, such as infections and tissue damage, which promote the activation of self-reactive lymphocytes These genetic and environmental influences conspire to create an imbalance between control mechanisms that normally function to prevent self-reactivity and pathways that lead to activation of pathogenic effector lymphocytes

Mechanism of Autoimmunity ROLE OF SUSCEPTIBILITY GENES Most autoimmune diseases are complex multigenic disorders HLA genes – affects the negative selection of T cells in the thymus or the development of regulatory T cells Non-MHC genes PTPN-22 = most frequently implicated in autoimmunity; encodes for the protein tyrosine phosphatase NOD-2 = cytoplasmic sensor of microbes; associated with Crohn disease Genes encoding the IL-2 receptor (CD25) and IL-7 receptor alpha chain = control the maintenance of regulatory T cells

Mechanisms of Autoimmunity ROLE OF INFECTIONS Infections may up-regulate the expression of costimulators on APCs Results in breakdown of anergy and activation of T cells specific for the self-antigens Molecular mimicry Microbes may express antigens that have the same amino acid sequences as self-antigens Immune responses against the microbial antigens may result in activation of self-reactive lymphocytes RHD – antibodies against streptococcal proteins cross-react with myocardial proteins Polyclonal B-cell activation Some viral infections may result in production of autoantibodies EBV and HIV

POSTULATED ROLE OF INFECTIONS IN AUTOIMMUNITY

Mechanisms of Autoimmunity RELEASE OF SEQUESTERD ANTIGENS  Some antigens are hidden (sequestered) from the immune system, because the tissues in which antigens are located do not communicate with the blood and lymph. self-antigens in these tissues do not induce tolerance but fail to elicit immune responses and are essentially ignored by the immune system Immune-privileged sites – testis, eye, and brain Trauma to these sites  release antigens  tissue inflammation and injury

General Features of Autoimmune Diseases Once induced it tends to be progressive, sometimes with sporadic relapses and remissions, and the damage becomes inexorable Epitope Spreading Infections and initial autoimmune response  damage tissues, release self antigens and exposed epitopes of the antigens that are normally concealed from the immune system  continuing activation of lymphocytes The clinical and pathologic manifestations of an autoimmune disease are determined by the nature of the underlying immune response Different autoimmune diseases show substancial clinical, pathologic, and serologic overlaps

Microbial infections associated with autoimmune diseases Multiple sclerosis Mixed cryoglobulinemia Allergic encephalitis Scleroderma VIRUSES Hepatitis B virus Hepatitis C virus Measles virus Cytomegalovirus Rheumatic fever Guillain-Barre syndrome Primary biliary cirrhosis Reiter’s syndrome Reiter’s syndrome Grave’s disease Lyme arthritis BACTERIA Streptococcus pyogenes Campylobacter jejuni Escherichia coli Chlamydia trachomatis Shigella sp. Yersinia enterocolitica Borrelia burgdorferi Autoimmune disease Microbe

ORGAN-SPECIFIC AUTOIMMUNE DISEASES Intrinsic factor and parietal cells BM of kidney & lung Islet cell Adrenal cortex Sperm Desmoglein in tight junctions of skin Thyroglobulin Thyroid peroxidase Pernicious anemia Goodpasture’s synd. IDDM Addison’s disease Male infertility Pemphigus Hashimoto’s Primary myxedema Antibody to cell components other than receptors Acetylcholine receptor TSH receptor Myasthenia gravis Grave’s disease Antibody to receptors Target of Immune Response Autoimmune Disease Type of Immune Response

NON-ORGAN SPECIFIC AUTOIMMUNE DISEASES IgG in joints dsDNA, histones RNP antigens (SS-A/Ro and SS-B/La) Myelin protein Rheumatoid arthritis SLE Sjogren’s syndrome (Sicca syndrome) Guillain-Barre synd. Antibody to cell components other than receptors Target of Immune Response Autoimmune Disease Type of Immune Response

Systemic Lupus Erythematosus (SLE) Etiology: Unknown Pathogenesis: Failure to maintain self-tolerance due to polyclonal autoantibodies Multisystem: Skin, kidneys, serosal surfaces, joints, CNS & heart Incidence: 1:2500 more common in black Americans; 10X F > M; 2nd- 3rd decades

SLE: Predisposing Factors Genetic factors 30% concordance in monozygotic twins Associated w/ HLA-DR 2 & 3 loci Non-genetic factors Drugs (procainamide, isoniazid, d- penicillamine & hydralazine)  LE like s/s Androgens protect, estrogens enhance UV light may trigger

SLE Immunologic factors B-cell hyper-reactivity caused by excess T-helper activity How self-tolerance is lost is not known

Model for the pathogenesis of SLE

MODEL FOR THE PATHOGENESIS OF SYSTEMIC LUPUS ERYTHEMATOSUS

Revised Criteria for Classification of SLE Malar rash Discoid rash Photosensitivity (Photodermatitis) Oral ulcers Arthritis Serositis- Pleuritis; Pericarditis Renal disorder Persistent proteinuria > 0.5 gms/ day or > 3+ if quantitation not performed, or; Cellular casts- red cell, hemoglobin, granular, tubular, or mixed

Revised Criteria for Classification of SLE Neurologic disorder- Seizures; Psychosis Hematologic disorder Hemolytic A with reticulocytosis PANCYTOPENIA Immunologic disorder: (+) LE cell prep; (+) Anti- dsDNA (+) Anti-Sm (+) Antiphospholipid antibodies Anticardiolipin antibodies (+) lupus anticoagulant False-positive serologic test for syphilis ANA

CLINICAL MANIFESTATIONS OF SLE 100 80-90 85 55-85 80-100 60 50-70 25-35 45 35 25 20 15-40 15 15 8 th Edition

Multisystem manifestations of Systemic Lupus Erythematosus. SLE affects a wide range of tissues and organ systems

Revised Criteria for Classification of SLE Any 4 or more of the 11 criteria present, serially or simultaneously, during any interval of observation = SLE In 1997, anti-phospholipid antibody was added to the list of criteria for the classification of SLE

SLE Antinuclear antibodies Antibodies to DNA (Classic SLE) Antibodies to histones (Drug induced SLE) Antibodies to non- histone proteins bound to RNA Antibodies to nucleolar antigens ANA test is sensitive, but non specific

SLE Mechanisms of tissue injury Type III hypersensitivity reactions with DNA-anti-DNA complexes depositing in vessels LE cell - any phagocytic leukocyte (neutrophil or macrophage) that engulfs denatured nuclei of injured cells (evidence of cell injury and exposed nuclei)

SLE: Morphology BV: Acute necrotizing vasculitis of small arteries or arterioles in any organs Skin: Erythematous maculopapular eruption over malar regions exacerbated by sun-exposure; some patients have discoid LE with no systemic involvement Liquefactive degeneration of basal layer Interface dermatitis w/ superficial & deep perivascular lymphocytic infiltrates w/ deposits of immunoglobulins along DEJ

SLE involving the skin. An H & E-stained section shows liquefactive degeneration of the basal layer of the epidermis and edema of the dermo-epidermal junction B. An IF micrograph stained for IgG reveals deposits of Ig along the dermo-epidermal junction

SLE Serosa: Pericardial & pleural serosanguinous exudate Heart: Nonbacterial verrucous endocarditis (Libman- Sacks) multiple warty deposits on any valve on either surface of leaflets

Libman-Sacks endocarditis of the mitral valve in lupus erythematosus. The vegetations attached to the margin of the thickened valve leaflet are indicated by arrows.

SLE Joint: No striking anatomic changes nor deformities, non- specific lymphocytic infiltrates Spleen: Splenomegaly, capsular thickening, and follicular hyperplasia Lungs: Pleuritis and pleural effusions CNS: Multifocal cerebral infarcts from microvascular injury Other Organs and Tissues: LE or hematoxylin bodiesnin the bone marrow or other organs. Lymph nodes may be enlarged with hyperplastic follicles or even demonstrate necrotizing lymphadenitis

SLE: Morphology- Renal Mesangial GN Mild s/s (10-25%) Focal Proliferative GN Mild s/s (20-35%) Diffuse Proliferative GN Hematuria, (35%- 60%) proteinuria & hypertension  renal failure Membranous GN Severe proteinuria (10-15%) & NS

Lupus nephritis, focal proliferative type. There are two focal necrotizing lesions in the glomerulus (arrows)

Lupus nephritis, diffuse proliferative type. There is marked increase in cellularity throughout the glomrulus

Immune complex deposition in SLE. IF micrograph of a glomrulus stained with anti-IgG from a patient with diffuse proliferative lupus nephritis.

Immune complex deposition in SLE. Electron micrograph of a renal glomerular capillary loop showing subendothelial dense deposits corresponding to “wire loops” seen by light microscopy. Deposits are also seen in the mesangium.

Lupus nephritis. A glomerulus with several “wire loop” lesions representing extensive subendothelial deposits of immune complexes.

Rheumatic Fever Etiology: Group A, streptococcal pharyngitis Pathogenesis: antibody cross-react with connective tissue in susceptible individuals  Autoimmune reaction (2- 3 wks)  Inflammation (T cells, macrophages)  Heart, skin, brain & joints

Morphology: Acute RF Acute Inflammatory Phase Heart– Pancarditis Skin– Erythema Marginatum CNS– Sydenham Chorea Migratory polyarthritis Chronic RF Deforming fibrotic valvular disease

Rheumatoid Arthritis: Etiology HLA- DR4/ DR1 associated (increased incidence) Incidence: 1% of population; 4 th & 5 th decades; 3 - 5X F > M 80% of patients with Rheumatoid Factors (Abs against Fc portion of IgG)

Rheumatoid Arthritis: Pathogenesis Precise trigger is unknown Activation of T-helper cells  cytokines  activate B cells  Abs  Non-suppurative proliferative synovitis (destruction of articular cartilage & progressive disabling arthritis) Extra-articular manifestations resemble SLE or scleroderma

Multisystem manifestations of Rheumatoid arthritis. Although the initial manifestation is usually arthritis, Rheumatoid disease is a systemic illness.

Rheumatoid Arthritis: Clinical course Symmetrical, polyarticular arthritis Weakness, fever, malaise may accompany joint symptoms Stiffness of joints in AM early  claw-like deformities Anemia of chronic disease present in late cases Severely crippling in 15-20 years, life expectancy reduced 4-10 years Amyloidosis develops in 5%-10% of patients

Rheumatoid Arthritis: Morphology Symmetric arthritis of small joints (proximal interphalangeal & metacarpophalangeal Chronic synovitis, proliferation of synovial lining cells (villous projections) Subsynovial inflammatory cells  lymphoid nodules Pannus- highly vascularized, inflamed, reduplicated synovium Fibrosis & calcification  ankylosis Synovial fluid contains neutrophils

Rheumatoid synovitis. The synovium is swollen and shows villous pattern. There is great increase in chronic inflammatory cells in the synovial stroma, often with exudate in the joint space and fibrin deposited on the synovial surface.

Articular cartilage destruction. Vascular granulation tissue grows across the surface of the carilage (pannus) from the edges of the joint, and the articular surface shows loss of cartilage beneath the extending pannus.

The inflammatory pannus causes FOCAL DESTRUCTION OF BONE. At the edges of the joint there is osteolytic destruction of bone. This phase is associated with joint deformity.

The characteristic deformity and soft tissue swelling associated with long-standing rheumatoid disease of the hands.

Rheumatoid Arthritis: Morphology Rheumatoid nodules (25% of patients) Subcutaneous nodules along extensor surfaces of forearms or other sites of trauma Firm, non-tender, up to 2 cm. diameter Dermal nodules with fibrinoid necrosis surrounded by macrophages & granulation tissue Progressive interstitial fibrosis of lungs some cases

Rheumatoid nodule. At the elbow there is a large raised subcutaneous nodule. The nodule is composed of degenerate collagen (arrow) surrounded by a chronic reaction with macrophages and giant cells, and walled off by fibrosis.

Juvenile Rheumatoid Arthritis Chronic idiopathic arthritis in children Some variants involve few large joints (pauciarticular) Do not have rheumatoid factor Others assoc. w/ HLA-B27 Uveitis may be present Still’s disease Acute febrile onset Leukocytosis Hepatosplenomegaly Lymphoadenopathy & skin rash

Sjogren’s Syndrome: Features Dry eyes (keratoconjunctivitis sicca) & dry mouth (xerostomia) due to immune destruction of the lacrimal and salivary glands Sicca syndrome- this phenomenon occurring as an isolated syndrome Frequently associated with RA, some with SLE or other autoimmune processes Associated with HLA- DR3

Sjogren’s syndrome: Pathogenesis Primary target is ductal epithelial cells of exocrine glands B-cell hyperactivity  hypergammaglobulinemia, ANAs Primary defect is in T-helper cells (too many) Most have anti -SS-A & anti-SS-B Abs

Sjogren’s syndrome: Clinical course Primarily in women > 40 Dry mouth, lack of tears Salivary glands enlarged Lacrimal & salivary gland inflammation of any cause (including Sjogren's) is called Mikulicz's syndrome 60% w/ other CTD 1% develop lymphoma, 10% w/ pseudolymphomas

Sjogren’s syndrome: Morphology All secretory glands can be involved Intense lymphoplasmacellular infiltrates 2ndary inflammation of corneal epithelium (due to drying)  ulceration & xerostomia Can develop respiratory symptoms 25% develop extraglandular disease (most with anti-SS-A) CNS, kidneys, skin & muscles

Systemic Sclerosis (Scleroderma) A chronic disease characterized by Chronic inflammation thought to be a result of autoimmunity Widespread damage to small blood vessels Progressive interstitial and perivascular fibrosis in the skin and multiple organs

Systemic Sclerosis (Scleroderma) Etiology: Unknown Most common in 3 rd - 5 th decades 3X as frequent in women as in men 95% w/ skin involvement Can be Diffuse or Limited

Systemic Sclerosis (Scleroderma) Pathogenesis: Abnormal immune responses CD4+ T cells responding to an unidentified antigen accumulates in the skin and release cytokines that activate inflammatory cell and fibroblasts Vascular damage Microvascular disease is consistently present early in the course of systemic sclerosis and may be the initial lesion Collagen deposition

Possible mechanisms leading to systemic sclerosis

Schematic illustration of the possible mechanisms leading to systemic sclerosis

Systemic Sclerosis (Scleroderma) Diffuse Scleroderma: Anti-DNA topoisomerase I (Scl-70) is highly specific in 75% of patients (nucleolar pattern of staining) Limited Scleroderma (CREST): Anti-centromere pattern in 60%-80% of patients Suggested that microvascular disease may play some role in development of fibrosis

Systemic Sclerosis: Clinical course Raynaud’s phenomenon reversible vasospasm of digital arteries  color changes; sensitivity to cold Fibrosis  joint immobilization Eosphageal fibrosis  dysphagia & GI hypomotility Pulmonary fibrosis  dyspnea & chronic cough  RSHF Malignant HPN (hyperplastic arteriolosclerosis)  renal failure 35%-70% 10 year survival with Diffuse SS

Systemic Sclerosis: Clinical course CREST (Limited Scleroderma) C alcinosis R aynaud’s phenomenon E sophageal dysmotility S clerodactyly (Dermal fibrosis) T elangiectasia Better long-term survival than Diffuse PSS

Multisystem manifestations of Systemic Sclerosis. Systemic Sclerosis affects a wide range of tissues and organ systems, often as a result of vascular obliteration.

The fingers in some patients with Systemic Sclerosis are narrowed, with tight shiny skin. Subcutaneous calcification (calcinosis cutis) can also be seen as white spots on the edges of the fingers.

Systemic Sclerosis: Morphology Skin: fingers & distal extremities then spreads, shows edema & inflammation  thickened collagen & epidermal atrophy; subcutaneous calcification (esp in CREST); Morphea- skin fibrosis only GI tract (80% of patients): atrophy & fibrosis of esophageal wall w/ mucosal atrophy, BV thickening

Systemic Sclerosis: Morphology MS: inflammatory synovitis  fibrosis  joint destruction; muscle atrophy Lungs: interstitial fibrosis (honeycomb) & BV thickening Kidneys: 66% concentric thickening of vessels 30% malignant hypertension (fibrinoid necrosis of arterioles) Heart: focal interstitial fibrosis & slight inflammation

Mixed Connective Tissue Disease Used to describe a disease with clinical features that are a mixture of the features of SLE, systemic sclerosis, and polymyositis Characterized serologically by high titers of antibodies to ribonucleoprotein particle-containing U1ribonucleoprotein

Polyarteritis Nodosa and Other Vasculitides Belongs to a group of diseases characterized by necrotizing inflammation of the walls of blood vessels and showing strong evidence of an immunological pathogenetic mechanism

Polymyositis- Dermatomyositis- inclusion body myositis Inflammation of skeletal muscle with weakness Sometimes associated w/ skin rash (dermatomyositis) Incidence: 40-60 also in 5-15 y/o, mostly in women Mainly mediated by cytotoxic CD8 cells In dermatomyositis, mainly ICs produce a vasculitis in muscle & skin Adults (10-20%) develop cancer

Polymyositis- Dermatomyositis- inclusion body myositis I. Adult polymyositis (w/o skin involvement nor visceral CA; CD8 mediated) II. Adult dermatomyositis (Ab mediated) III. Polymyositis or dermatomyositis w/ malignancy IV. Childhood dermatomyositis V. Polymyositis or dermatomyositis w/ immunologic disease

Polymyositis- Dermatomyositis- inclusion body myositis Immunologic abnormality: Anti PM 1 & anti Jo Pathology: Striated muscles: necrosis, regeneration, mononuclear infiltrates & atrophy of symmetric proximal muscle groups Skin: Heliotrope rash; Grottons lesions

DERMATOMYOSITIS Take note of the rash affecting the eyelids.

DERMATOMYOSITIS The histologic appearance of muscle shows fascicular inflammation and atrophy.

INCLUSION BODY MYOSITIS Shows a vacuole within a myocyte.

Polymyositis- Dermatomyositis- inclusion body myositis: Diagnosis Location of muscles involved Elevation of CPK MM EMG Biopsy Cutaneous lesions

ANTINUCLEAR ANTIBODIES IN VARIOUS AUTOIMMUNE DISEASES

IMMUNODEFICIENCY SYNDROMES Primary immunodeficiency disorders Almost always genetically determined Affect the humoral and/or cellular arms of adaptive immunity or the defense mechanisms of innate immunity Secondary immunodeficiency states May arise as complications of cancers, infections, malnutrition, or side-effects of immunosuppression, irradiation, or chemotherapy for cancer and other diseases

IMMUNODEFICIENCY SYNDROMES Risk factors for immune disorders Prematurity Autoimmune diseases (e.g., SLE) Lymphoproliferative disorders Infections (e.g., HIV) Immunosuppressive drugs (e.g., corticosteroids)

Simplified scheme of lymphocyte development and sites of block in primary immunodeficiency diseases

PRIMARY IMMUNODEFICIENCIES X-linked Agammaglobulinemia of Bruton ◘ Failure of B-cell precursors ( pro-B cells and pre-B cells) to differentiate into B cells ◘ maturation stops after the rearrangement of heavy- chain genes; light chains are not produced ◘ the block in differentiation is due to mutations in a cytoplasmic tyrosine kinase – Bruton tyrosinase kinase ( btk )

PRIMARY IMMUNODEFICIENCIES X-linked Agammaglobulinemia of Bruton ◘ seen almost entirely in males but sporadic cases seen in females ◘ does not become apparent until about 6 months of life ◘ recurrent bacterial infections of the respiratory tract call attention to the underlying immune defect – H. influenzae, S. pneumoniae, or S. aureus ◘ 35% of children develop arthritis that respond to Ig therapy ◘ SLE and Dermatomyositis occur with increased frequency ◘ Treatment is replacement therapy with Ig

PRIMARY IMMUNODEFICIENCIES X-linked Agammaglobulinemia of Bruton Characteristics: ◘ B cells are absent or remarkably decreased and serum classes of all Ig are depressed ◘ Germinal centers of LN, Peyer’s patches, the appendix, and tonsils are underdeveloped or rudimentary ◘ there is remarkable absence of plasma cells throughout the body ◘ T cell-mediated reactions are entirely normal

PRIMARY IMMUNODEFICIENCIES 2. Common Variable Immunodeficiency ◘ Feature common to all patients is hypogammaglobulinemia, generally affecting all classes of antibody but sometimes only IgG ◘ Diagnosis is based on exclusion of other well-defined causes of decreased antibody synthesis ◘ No evidence of any intrinsic B cell defect

PRIMARY IMMUNODEFICIENCIES Common Variable Immunodeficiency ◘ Clinical manifestations resemble X-linked agammaglobulinemia ◘ 20% of patients have recurrent herpesvirus infections ◘ Affects both sexes equally ◘ Onset of symptoms is later – in childhood or adolescence ◘ Histologically, B cell areas of lymphoid tissues are hyperplasplastic ◘ Increased incidence of RA, PA, HA, lymphoid malignancy, and gastric cancer (50-fold)

PRIMARY IMMUNODEFICIENCIES 3. Isolated IgA deficiency ◘ Affected individuals have extremely low levels of both serum and secretory IgA ◘ Most individuals with this disease are completely asymptomatic ◘ Mucosal defenses are weakend and infections occur in the respiratory, gastrointestinal and urogenital tracts ◘ Symptomatic patients commonly present with recurrent sino-pulmonary infections and diarrhea

PRIMARY IMMUNODEFICIENCIES Isolated IgA deficiency ◘ Basic defect is in the differentiation of IgA B lymphocytes ◘ In most patients, the number of IgA positive B cells is normal, but only few of these cells can be induced to transform into IgA plasma cells in vitro ◘ Serum antibodies to IgA are found in approximately 40% of the patients ◘ Fatal anaphylactic reactions occur if transfused with blood containing normal IgA

PRIMARY IMMUNODEFICIENCIES 4. Hyper IgM Syndrome ◘ Affected patients make IgM antibodies but are deficient in their ability to produce IgG, IgA, and IgE antibodies ◘ A T cell disorder in which functionally abnormal T cells fail to induce B cells to make antibodies of isotypes other than IgM ◘ Clinically, male patients with the X-linked form present with recurrent pyogenic infections, susceptible to Pneumocystis carinii pneumonia ◘ Serum of patients contains normal or elevated levels of IgM and IgD but no IgA or IgE and extremely low levels of IgG

PRIMARY IMMUNODEFICIENCIES 5. DiGeorge Syndrome (Thymic Hypoplasia) ◘ T cell deficiency that derives from failure of development of the 3 rd and 4 th pharyngeal pouches – thymus, parathyroids, some clear cells of the thyroid, and ultimobranchial body ◘ Variable loss of T cell-mediated immunity, tetany, congenital defects of the heart and great vessels ◘ Appearance of the mouth, ears, and facies maybe abnormal

PRIMARY IMMUNODEFICIENCIES DiGeorge Syndrome (Thymic Hypoplasia) ◘ Low levels of circulating T lymphocytes and a poor defense against certain fungal and viral infections ◘ Plasma cells are present in normal numbers in lymphoid tissues; depleted in paracortical areas of the LN and periateriolar sheaths of spleen ◘ Ig levels maybe normal or reduced, depending on the severity of the T cell deficiency

PRIMARY IMMUNODEFICIENCIES DiGeorge Syndrome (Thymic Hypoplasia) ◘ Partial DiGeorge syndrome – small but histologically normal thymus, T cell function improves with age ◘ Complete absence of thymus – transplantation of fetal thymus may be of benefit ◘ A component of 22q11 deletion syndrome

PRIMARY IMMUNODEFICIENCIES 6. Severe Combined Immunodeficiency Diseases ◘ Involves both humoral and cell-mediated immune responses ◘ Affected infants present with oral candidiasis, extensive diaper rash, and failure to thrive ◘ Definitive treatment – bone marrow transplantation

PRIMARY IMMUNODEFICIENCIES Severe Combined Immunodeficiency Diseases ◘ Classic Form – defect in the common lymphoid stem cell ◘ X-linked – genetic defect is mutation in the common γ chain subunit ( γ c) of several cytokine receptors ◘ Autosomal recesive – deficiency of the adenosine deaminase (ADA) enzyme = leads to accumulation of deoxyadenosine and its derivatives which are toxic to immature lymphocytes esp. of T cell lineage ***histologic findings = small thymus devoid of lymphoid cells

PRIMARY IMMUNODEFICIENCIES 7. Immunodeficiency with Thrombocytopenia and Eczema (Wiskott-Aldrich Syndrome) ◘ X-linked recessive disease char. by thrombocytopenia, eczema, and a marked vulnerability to recurrent infection ending in early death ◘ Thymus is morphologically normal, but there is progressive secondary depletion of T lymphocytes in the peripheral blood and in the paracortical areas of LN ◘ IgM is low; IgG normal; IgA & IgE elevated ◘ The syndrome maps to Xp11.23 – inc. lymphoma ◘ Treatment is bone marrow transplantation

PRIMARY IMMUNODEFICIENCIES 8. Genetic Deficiencies of the Complement System ◘ Deficiency of C2 is the most common = inc. incidence of SLE-like disease ◘ Deficiency of C3 = serious and recurrent pyogenic infections = immune complex-mediated GN ◘ C5, 6, 7, 8, and 9 = increased susceptibility to recurrent neisserial infections ◘ C1 inhibitor deficiency = hereditary angioedema

ACQUIRED IMMUNODEFICIENCY SYNDROME ◘ A retroviral disease characterized by by profound immunosuppression that leads to opportunistic infections, secondary neoplasms, and neurologic manifestations ◘ Second leading cause of death in men 25-44 years old ◘ 3 rd leading cause of death in women

HUMAN IMMUNODEFICIENCY VIRUS (HIV) Etiologic agent of AIDS Discovered independently by Luc Montagnier of France and Robert Gallo of the US in 1983-1984 Former names of the virus include : Human T cell Lymphotrophic virus (HTLV-III) Lymphadenopathy associated virus (LAV) AIDS associated retrovirus (ARV) ***HIV-2 discovered in 1986, antigenically distinct virus endemic in West Africa

ACQUIRED IMMUNODEFICIENCY SYNDROME ◘ Groups at risk of developing AIDS 1. Homosexual or bisexual men – over 50% 2. Intravenous drug abusers – 20% 3. Hemophiliacs – 0.5% 4. Recipients of blood and blood components – 1.0% 5. Heterosexual contacts of members of other high-risk groups – 10%

ACQUIRED IMMUNODEFICIENCY SYNDROME ◘ 2% of all cases occurs under 13 years old, 90% of these resulted from transmission of the virus from mother to child, remaining 10% are hemophiliacs or received blood/blood products ◘ 3 major routes of transmission 1. sexual transmission – 75% 2. parenteral transmission  IV drug users, hemophiliacs, BT 3. mother-to-infant transmission

ACQUIRED IMMUNODEFICIENCY SYNDROME ◘ mother-to-infant transmission – pediatric AIDS 1. in utero by transplacental spread 2. during delivery through an infected birth canal 3. after birth by ingestion of breast milk ☻☻ Extensive studies indicate that HIV infection cannot be transmitted by casual personal contact in the household, workplace, or school ☻☻ Seroconversion after needle-stick injury – 0.3%

ACQUIRED IMMUNODEFICIENCY SYNDROME ◘ Etiology: 1. HIV-1 – most common type associated with AIDS in the US, Europe, and Central Africa 2. HIV-2 – West Africa and India

ACQUIRED IMMUNODEFICIENCY SYNDROME ◘ Contents of the viral core 1. major capsid protein p24 2. nucleocapsid protein p7/p9 3. two copies of genomic RNA 4. three viral enzymes – protease, reverse transcriptase, and integrase ۞ p24 most readily detected viral antigen hence the target for the antibodies used for diagnosis

Schematic illustration of an HIV-1 virion

HIV proviral genome. Several viral genes and their corresponding functions

Life cycle of HIV, showing the steps from viral entry to production of infectious virions

Molecular basis of HIV entry into host cells.

Pathogenesis of HIV-1 infection.

Mechanisms of CD4+ T-cell loss in HIV infection

Multiple effects of loss of CD4 + T cells as a result of HIV infection

CDC Classification Categories of HIV infection AIDS, indicator conditions: constitutional disease, neurologic disease, or neoplasm B3 B2 B1 Symptomatic, not A nor C conditions A3 A2 A1 Asymptomatic, acute (primary) HIV, or persistent generalized lymphadenopathy 3 <200 cells/uL 2 200-499 cells/uL 1 > 500 cells/uL Clinical Categories

Typical course of HIV infection

Algorithm for Serologic Testing for AIDS

AMYLOIDOSIS ◘ Amyloid is a pathologic proteinaceous substance, deposited in between cells in various tissues and organs of the body in a wide variety of clinical settings ◘ Appears as an amorphous, eosinophilic, hyaline, extracellular substances that, with progressive accumulation, encroaches on and produces pressure atrophy of adjacent cells

Structure of an amyloid fibril

A section of the liver stained with Congo Red Yellow-green birefringence of the deposits observed under polarizing microscope

AMYLOIDOSIS ◘ Chemical nature - 95% consist of fibril proteins, 5% P component and other glycoproteins - 3 most common amyloid proteins 1. AL (amyloid light chain) – derived from plasma cells and contains Ig light chains 2. AA (amyloid-associated) – non-Ig protein synthesized by the liver 3. A β amyloid – found in Alzheimer disease ◘ Other biochemical distinct proteins found in amyloid deposits - Transthyretin (TTR), β 2-microglobulin, prion proteins

Types of Amyloidosis 1. Systemic Similar tissue involvement in both primary and secondary types Primary amyloidosis AL amyloid deposition Associated with multiple myeloma (30% of cases) Secondary (reactive) AA amyloid Associated with chronic inflammation (e.g., RA, Tb)

Types of Amyloidosis 2. Localized Confined to a single organ (e.g. brain) Alzheimer’s disease A ß Most common cause of dementia 3. Hereditary Autosomal recessive disorder involving AA amyloid (e.g., Familial Mediterranean fever)

AMYLOIDOSIS Pathogenesis Abnormal folding of proteins, which are deposited as fibrils in extracellular tissues and disrupt normal function

Proposed mechanisms in the pathogenesis of amyloidosis

Amyloidosis - Morphology ◘ Gross – Affected organs are often enlarged and firm and have a waxy appearance. - Painting the cut surface with iodine imparts a yellow color that is transformed to blue violet after application of sulfuric acid ◘ Microscopic – Based almost entirely on its staining characteristics (Congo Red)

Amyloidosis - Morphology ◘ Kidney - most common and potentially the most serious form of organ involvement - may appear normal in size and color or it may be enlarged in advanced cases - it may be shrunken and contracted due to vascular narrowing induced by amyloid deposits - deposited primarily in glomeruli, but also affected are the interstitial peritubular tissue, arteries, and arterioles

Amyloidosis - Morphology ◘ Kidney  thickening of the mesangial matrix + uneven widening of the basement membrane of glomerular capillaries  capillary narrowing and distortion of glomerular vascular tuft  obliteration of capillary lumens  masses or interlacing broad ribbons of amyloid

Amyloidosis of the kidney. The glomerular architecture is almost totally obliterated by the massive accumulation of amyloid

Amyloidosis - Morphology ◘ Spleen - inapparent grossly or may cause moderate to marked splenomegaly (up tp 800 grams) - Sago spleen  deposit limited largely the the splenic follicles, producing tapioca-like granules on gross inspection - Lardaceous spleen  involves the walls of the splenic sinuses and connective tissue framework in the red pulp. Fusion of the early deposits gives rise to large, maplike areas of amyloidosis

Amyloidosis - Morphology ◘ Liver - grossly inapparent or cause moderate to marked hepatomegaly - appears first in the space of Disse  encroach on adjacent hepatic parenchymal cells and sinusoids  deformity, pressure atrophy, disappearance of hepatocytes - Vascular involvement and Kupffer cell depositions are frequent - Normal liver function is usually preserved

Amyloidosis - Morphology ◘ Heart - may be enlarged and firm, shows no significant changes on cross-section of the myocardium - deposits begin in subendocardial accumulations and within the myocardium between the muscle fibers  expansion  pressure atrophy - conduction system damaged leads to electrocardiographic abnormalities

Amyloidosis - Morphology ◘ Other organs - encountered in systemic disease - adrenals, thyroid, and pituitary - GIT - tongue – tumor-forming amyloid of the tongue - Respiratory tract - Brain – Alzheimer’s disease - Peripheral and Autonomic nerves - median nerve – carpal tunnel syndrome

Diseases Of Immunity

More Related Content

What's hot

Similar to Diseases Of Immunity

More from MD Specialclass

Recently uploaded

Diseases Of Immunity

Editor's Notes