AUTOIMMUNE

DR. ABDUL O.A

AUTOIMMUNE DISEASES

• Autoimmunity is a state in which the body

immune system fails to distinguish b/w self
and non-self
• Rxns by formation of Autoantibodies against
one’s own tissue Ags
• Loss of tolerance to one’s own tissue
• Autoimmunity is the opposite of Immune
Tolerance
• Immune Tolerance is a normal phenomenon
present since foetal life
• Defined as the ability of an individual to
recognize self tissue and Ags
• Normally immune system does this by:
• Clonal elimination
• Concept of clonal anergy
• Suppressor T cells
• Central tolerance occurs DURING lymphocyte
development and operates in the thymus and bone
marrow
• Here, T and B lymphocytes that recognize self
antigens are deleted before they develop into fully
immunocompetent cells, preventing autoimmunity
• Peripheral tolerance is immunological tolerance
developed AFTER T and B cells mature and enter
the periphery
• Acquired or induced tolerance refers to the immune system's
adaptation to external antigens xterized by a specific non-
reactivity of the lymphoid tissues to a given antigen
• One of the most important natural kinds of acquired
tolerance is immune tolerance in pregnancy, where the foetus
and the placenta must be tolerated by the maternal immune
system
• Anergy is a term in that describes a lack of reaction by the
body's defense mechanisms to foreign substances
• And consists of a direct induction of peripheral lymphocyte
tolerance
• Acquired or induced tolerance refers to the immune system's
adaptation to external antigens xterized by a specific non-
reactivity of the lymphoid tissues to a given antigen
• One of the most important natural kinds of acquired
tolerance is immune tolerance in pregnancy, where the foetus
and the placenta must be tolerated by the maternal immune
system
• Anergy is a term in that describes a lack of reaction by the
body's defense mechanisms to foreign substances
• And consists of a direct induction of peripheral lymphocyte
tolerance
 Pathogenesis of Autoimmunity

• Immunological, genetic and microbial

Immunological factors
• Failure of immunological mechanism of tolerance
initiate autoimmunity
- Polyclonal activation of B cells
- Generation of self-reacting B cell clone
- Decreased T suppressor and increase T helper cell
activity
- Functionality of anti-idiotypic network control
may cause failure of mechanism of immune tolerance
 - Sequestered Ag released from tissues ->
act as foreign Ag. if introduced into circulation later
• E.g. trauma to testis -> formation of anti-sperm Abs
against spermatozoan
• Genetic factors
Evidences are:
• Increased expression of Class II HLA Ag on tissues
involved in autoimmunity
• Increased familial incidence of some of the AIDs
Microbial factors
• Infection with microorganisms, especially
viruses (EBV) and less often bacteria (e.g.
streptococci, klebsiella) and mycoplasma, has
been implicated in the pathogenesis of AIDs
• STRONG GENETIC PREDISPOSITION
• OFTEN RELATED TO OTHER AUTOIMMUNE
DISEASES
• OFTEN TRIGGERED BY INFECTIONS
Types and Examples of AIDs:
• Organ specific Diseases – AutoAbs formed rxns
specifically against tissue or organ -> chronic inflamm
destruction
• E.g. Endocrine glands like Thyroid, Pancreatic islets of
Langerhan, Adrenal cortex, Alimentary tract, Blood cells
• Organ non-specific (systemic) Diseases
• A number of AutoAbs are formed which rxn with Ags in
many tissues -> systemic lesions
• E.g. various systemic collagen diseases
 Examples of Systemic AIDs

• Systemic Lupus Erythematosus (SLE)

• Rheumatoid Arthritis
• SJÖGREN Syndrome
• Systemic Sclerosis (scleroderma)
• Mixed Connective Tissue Disease (MCD)
• PolyArteritis Nodosa (PAN)
• Reiter’s Syndrome
• Wegener Granulomatosus
 Examples of Organ specific (Localized) AIDs

ENDOCRINE
• Hashimoto (Autoimmune) Thyroiditis
• Graves Disease
• Type 1 DM
• Idiopathic Addison’s disease
ALIMENTARY TRACT
• Autoimmune atrophic gastritis
• Ulcerative colitis
• Crohn’s disease
BLOOD CELLS
• AutoImmune Haemolytic Anaemia (AIHA)
• AutoImmune Thrombocytopenia (ITP)
• Pernicious Anaemia
OTHERS
• Myasthenia Gravis
• Autoimmune orchiditis
• Autoimmune Encephalomyelitis
• Goodpasture’s Syndrome
• Primary Biliary Cirrhosis
• Membranous Glomerulonephritis
• Autoimmune skin diseases
• Is the classical example of systemic
Autoimmune or Collagen disease
• LUPUS = wolf -> believe to affect skin only and
eat away skin like wolf
• Two forms – SLE and Discoid LE
Aetiology
• Unknown, but a number of autoAbs against
nuclear and cytoplasmic components of the
cells are present
Examples:
• Antinuclear Abs (ANAs) – are the Abs against common
nuclear Abs that include DNA and RNA
• Seen in 98% of cases, hence best for screening test
• Abs to DS DNA (Anti-ds DNA) is most specific for SLE
especially in high titres, present in 70% of cases
• Anti-Smith Abs (anti-Sm) – Abs appear against smith
Ags is part of ribonucleoprotein
• Also specific, but is seen in about 25%
• Other non-specific Abs are:
• Anti-Ribonucleoprotein (Anti-RNP)
• Seen in 40% of cases of SLE, but more often seen in
Sjogren Syndrome
• Anti-histone Ab – Ab against histone ass with DNA in
chromatin, seen in drug-induced Lupus than SLE
• Anti-Phospholipid Abs or Lupus Anticoagulant are
tests for thrombotic complications in cases of SLE
• Antiribosomal P Ab – Ab against protein in ribosomes
and is seen in CNS lupus
• Source of these AutoAbs is the polyclonal
activation of B cells brought about by the
following derangements
• Immunological factors:
An inherited defect in B cells
Stimulation of B cells by microbes
T helper cell hyperactivity
T suppressor cell defect
• Genetic factors – due to the
immunoregulatory function of Class II HLA
genes implicated in the pathogenesis of SLE
• Other factors
Such as drugs e.g. penicillamine D
Certain viral infections e.g. EBV
Certain hormones -> oetrogens
• AutoAbs formed the mediators of tissue injury in SLE
• Type II hypersensitivity xterized by formation of
AutoAbs against blood cells (RBCs, Platelets,
Leucocytes) -> haematological derangement in SLE
• Type III hypersensitivity =- xterized by Ag-Ag complex
(commonly DNA-antiDNA Ab, sometimes Ig-coated
Ab complex) which is deposited at sites such as renal
glomeruli, walls of small BVs
• Widespread organs (visceral organs and
erythematous cutaneous eruptions)
• Serosal linings (pleuritic, pericarditis, synovitis)
• Spleen (vasculitis)
• Liver (portal triaditis)
• Lungs (intestinal pneumonitis, fibrosing alveolitis)
• CNS (vasculitis)
• Blood (AIHA, Thrombocytopenia)
LUPUS NEPHRITIS
• E/M – Large deposits in mesangium, subepithelial or
subendothelial
• I/M – Granular deposits of immune complex (IgG and
C3) on capillary mesangium and tubular basement
membranes
• WHO 6 classes of lupus Nephritis
• Class I – Minimal Disease seen in <5%
• L/M show no change
• I/F shows mesangial deposit
• Class II – Mesangial proliferation in 10-25%
• L/M shows mesangial hypercellularity
• I/F shows subepithelial or subendothelial
deposits
• Class III – Focal lupus Nephritis in 20-35%
• L/M focal or segmental endothelial and
mesangial cell proliferation in <50%
• Three subclasses:
• Class III A – Active lesions (focal proliferative)
• Class III A/C – Active on chronic (Focal
proliferative and sclerosing)
• Class III C – Chronic inactive lesions with scar
(focal sclerosing)
• Class IV - Diffuse lupus Nephritis seen in 35-60%
• L/M shows diffuse, segmental or global involvement of
>50% glomeruli, proliferation of endothelial, mesangial
and epithelial cells, epithelial crescents
• I/F shows diffuse subendothelial deposits
• Two subclasses:
• Class IV-S 50% of involved glomeruli have segmental
lesion
• Class IV-G 50% of involved glomeruli have global lesion
• Class V – Membranous lupus Nephritis seen
in 10-15% cases
• L/M shows diffuse BM thickening
• I/F shows global or segmental subepithelial
deposits
• Class VI – Advanced sclerotic lupus Nephritis
seen in end stage diseases
• L/M shows global sclerosis of ≥90% glomeruli
Blood Vessel lesions (Acute Necrotizing Vasculitis)
• Affects all tissues, commonly skin and muscles
• L/M shows fibrinoid deposits in the vessel wall, perivascular
infiltration of mononuclear cells
Cutaneous Lesions (Erythematous eruptions)
• Butterfly area on nose or cheek
• L/M shows: Liquefactive degeneration of basal layer of epidermis
• Oedema at dermoepidermal junction
• Acute necrotizing vasculitis in dermis
• I/F shows immune complex deposits (IgG and C3) at
dermoepidermal junction
Cardiac lesions (Libman-Sacks Endocarditis)
• Vegetations on mitral and triscupid valves
• Extends to mural endocardium, chordae tendinae
• L/M of vegetations shows fibrinoid material,
necrotic debris, inflamm cells, haematoxylin bodies
• May be present on CT of endocardium and
myocardium
• May show focal inflamm and necrotizing vasculitis
• Middle aged woman
• Fatigue
• Myalgia
• Fever
• Weight loss
• Anaemia
• Organ related manifestations
• Claw-like flexion deformity of hands
• Raynaud’s phenomenon
• Oesophageal fibrosis causing dysplasia and
hypomotility
• Malabsorption syndromes
• Respiratory disorders
• Malignant HTN
• Pulmonary HTN
• Biliary cirrhosis
• To make a diagnosis, four or more of the following
diagnostic criteria need to be fulfilled:
• Molar rash xterized by fixed erythema, flat or raised,
over malar (zygomatic bone) eminence
• Discoid rash xterized by erythematous circular raised
patches with keratotic scaling or follicular plugging
• Photosensitivity seen as rash on exposure to sunlight
• Oral ulcers – extending to nasopharyxn
• Non-erosive arthritis affecting one or more joints
• Serositis (pleuritis or pericarditis)
• Renal manifestations seen as proteinuria
>0.5gm/day (≥3+) and cellular casts
• CNS manifestations such as siezure or psychosis
• Haematological derangements such as HA or
thrombocytopenia (<100,000/µl) or leucopenia
(>4,000/µl)
• Immunological derangements seen as positive
tests for anti-dsDNA, anti-Sm, and/or anti-
phospholipid AB
• Antinuclear Abs by I/F
Clinical course
• Usually runs a long course of flare-ups and
remissions
• Renal failure is the commonest cause of death
 Rheumatoid Arthritis
• Rheumatoid arthritis is a systemic autoimmune
disorder
• It involves the synovial membrane of multiple joints
• Women are more likely to be affected than men and
usually strikes between the ages of 20 and 40
• Spontaneous remission may be experienced by some
patients otherwise the disease may progress and
result in deformity and disability
• RA has been associated with certain of the HLA class
II molecules.
• HLA-DR1 and DR4 occur in 70% of patients with RA
• Clinical Signs:
• Diagnosis of RA is based on the 1987 criteria
established by the American College of Rheumatology
• Symptoms include morning stiffness around the joints
lasting at least 1 hour, swelling of the soft tissue
around three or more joints
• Others include swelling of the proximal interphalangeal,
metacarpophalangeal, or wrist joints, symmetric
arthritis, subcutaneous nodules, a positive RF test
• Also included is a radiographic evidence of erosion of the
joints of the hands, the wrist, or both
• Usually begins with nonspecific symptoms such as fever,
malaise, weight loss, and transient joint pain
• Stiffness and joint pain that gradually improves during
the day are characteristics exhibited by most patients
• Joint are involved progressively to larger
joints in a symmetric manner from the knees,
hips, elbows, shoulders and cervical spine
• About 25% of patients have nodules over the
bones
• Nodules may also be found in the myocardium,
pericardium, heart valve, pleural, lungs, spleen,
and larynx
• Immunologic Findings:
• The main immunologic finding is the presence of RF
• RF is a 19S Ab directed against the Fc portion of IgG
• The Ab is not specific for RA as it is found in other
diseases such as SLE, scleroderma, Sjögren’s
syndrome and B cell lymphoproliferative disorders
• It has been suggested that RF may be anti-idiotypic
antibodies involved in the regulation of immune
response
• In RA, polyclonal activation of B cells may occur
resulting in overwhelming amount of antibody to IgG
• Other autoAbs associated with RA include ANA, anti-
collagen Abs, Abs against cytoskeleton filamentous
proteins etc.
• These Abs may cause immune complex formation with
the activation of complement which contribute to
pathogenesis
• Joint damage is due to invasion of inflammatory cells
such as neutrophils, and macrophages
• Proliferation of fibroblast, macrophages, mast cells,
and stellar cells result in the formation of a pannus, an
organized mass of cells that grow into the joint space
• Laboratory Diagnosis of Rheumatoid Arthritis:
• Diagnosis is based on a combination of clinical
manifestations, radiographic findings and lab tests
• Laboratory screening test for RF using sheep red cells
or latex particles are available and simple to perform
• Quantitative test are also available which involve
nephelometry and ELISA techniques
• RF is found in other diseases such as syphilis, viral
infections, leprosy, chronic liver disease, neoplasm and
other inflammatory processes
• The RF test is thus not a specific test for RA
and about 10% of patient with the disease test
negative for RF
• C-reactive protein and ESR are usually
elevated and complements are normal or
elevated
 Hashimoto’s Thyroiditis

• Hashimoto’s thyroiditis and Graves’ disease are organ

specific autoimmune diseases
• Both diseases interfere with the thyroid gland
function
• The thyroid gland located in the anterior region of the
neck consist of units called follicles
• Follicles are lined with cuboidal epithelial cells and
filled with colloid
• The primary constituent of colloid is thyroglobulin
which is made up of triiodothyronine (T3) thyroxine
(T4)
• TRH acts on the pituitary gland to induce the release
of TSH
• TSH binds to receptors on the cell membrane of the
thyroid gland causing break down of thyroglobulin into T3
and T4
• AutoAbs may interfere with this process and cause under
or overactivity of the thyroid
• Hashimoto’s thyroditis is most often seen in women
between the ages of 30 and 40 years
• Patients develop a combination of goiter or enlarged
thyroid, hypothyroidism and thyroid autoantibodies
• An association with HLA antigens DR4 and DR5 has been
noted. DQA1 and DQB1 genes seem to confer resistance
• Immunologic Findings:
• Lymphocytic infiltration is seen with development of
germinal centers that almost replace the normal
glandular architecture of the thyroid
• Cell infiltrates include T and B cells, macrophages and
plasma cells
• Both CD4 and CD8 cells are found thus the disease is
characterized by a cellular and a humoral response
• Autoantibodies are found in up to 80% of cases
• Laboratory Testing:
• The autoantibodies present include Abs to
thyroglobulin and to thyroid microsomal antigen now
known as thyroid peroxidase
• Some peroxidase Abs inhibit enzyme activity while
others may mediate the cytotoxicity due to natural
killer cells
• Abs to thyroglobulin help to produce hypothyroid
conditions
• Other Abs include colloid Ab (CA2) thyrotropin-
binding inhibitory immunoglobulin (TBII)
• Others are thyroid stimulating immunoglobulin (TSI)
and thyroid growth-stimulating immunoglobulin (TGSI)
• Peroxidase Abs can be measured by particle
agglutination assays, complement fixation, RIA and
Indirect IFA
• Abs to thyroglobulin can be measured by precipitaion
in agar, indirect IFA, passive agglutination, RIA, and
EIA
• Indirect IFA use human or monkey thyroid tissue
fixed to a slide
• Antithyroglobulin Abs are found in about 80% of
patients with the disease
• THANK YOU