DISEASES OF THE IMMUNE

SYSTEM
Dr Fred Maate
19 April 2023
University of Zambia
School of Medicine
Department of Pathology and Microbiology
Outline
• Normal immune system
• Diseases of the immune system
• Hypersensitivity reactions
• Autoimmune diseases
• Immunodeficiency states
• Transplant medicine
• Amyloidosis
Normal immune system
Normal immune system
• Inert and adaptive
• Adaptive
• Humoral
• Cellular immunity
• Lymphoid organs
• Primary organs- BM and Thymus
• Secondary lymphoid organs- Lymph nodes, Spleen, MALT
DISEASES OF THE IMMUNE
SYSTEM
Diseases of the immune system
• Hypersensitivity reactions
• Autoimmune diseases
• Immunodeficiency states
• Graft vs host disease
• Amyloidosis
HYPERSENSITIVITY REACTIONS
Hypersensitivity reactions
• Type 1- Immediate type hypersensitivity
• Type 2- Antibody mediated hypersensitivity
• Type 3- Immune complex associated hypersensitivity reactions
• Type 4- Delayed type- hypersensitivity reactions
Hypersensitivity reactions
Type 1 hypersensitivity
• Immediate excessive immune reaction to an antigen that an
individual was previously exposed to the antigen has.
• Typical conditions are allergic reactions
• Involve first exposure to antigen
• IgE produced by plasma cells at first exposure is attached to mast cells
• CD4+ TH2 cells produce IL-12 that activates B cells resulting in class-switching
of B-cells to produce IgE
• Cross-linking of IgE on the surface of mast cells at second exposure
results in degranulation of mast cells
Type 1 hypersensitivity
• Early phase reaction- produced by mast cells degranulation products
• Late phase reaction- produced by inflammatory/ immulogic cells that
come to the site of reaction.
Examples Hypersensitivity type 1
• Asthma
• Hives
• Allergic rhinitis
Type 2 hypersensitivity
• Antibody driven
• Three main mechanisms
• Antibody-driven cellular dysfunction
• Antibodies activates hormone rectors- Graves disease
• Antibodies block receptors for neurotransmitter- Myasthenia gravis
• Opsonization and phagocytosis-
Antibodies activate complement to target cells for destruction by phagocytes-
• Autoimmune hemolytic anemia
• Complement and Fc- receptor-mediated inflammation-
• Goodpasture syndrome
Type 3 hypersensitivity reactions
• Immune complex deposition
• Antigen-antibody complexes produce tissue damage mainly by
eliciting inflammation at the sites of deposition
Type 3 hypersensitivity reactions
Type 4 hypersensitivity reactions
• Driven by
Mechanisms in delayed type hypersensitivity
reactions
Type 4 hypersensitivity reactions
Example of granuloma formation
AUTOIMMUNE DISEASES
Autoimmune disease
• Requirements to define as autoimmune disease
• the presence of an immune reaction specific for some self antigen or self
tissue
• evidence that such a reaction is not secondary to tissue damage but is of
primary pathogenic significance;
• the absence of another well-defined cause of the disease
Immunologic Tolerance and Autoimmunity
Tolerance (unresponsiveness) to self antigens is a fundamental property of the
immune system,
Breakdown of tolerance is the basis of autoimmune diseases.
Central tolerance: immature lymphocytes that recognize self antigens in the central
(generative) lymphoid organs are killed by apoptosis; in the B-cell lineage, some of
the self-reactive lymphocytes switch to new antigen receptors that are not self-
reactive.
Peripheral tolerance: mature lymphocytes that recognize self antigens in peripheral
tissues become functionally inactive (anergic), or are suppressed by regulatory T
lymphocytes, or die by apoptosis.
The factors that lead to a failure of self-tolerance and the development of
autoimmunity include (1) inheritance of susceptibility genes that may disrupt
different tolerance pathways, and (2) infections and tissue injury that may expose
self antigens and activate APCs and lymphocytes in the tissues.
Systemic Lupus Erythematosus
(SLE)
Antinuclear antibodies
• antibodies to DNA,
• antibodies to histones,
• antibodies to nonhistone proteins bound to RNA, and
• antibodies to nucleolar antigens
SLE Diagnostic criteria
• A person is said to have SLE if any four or more of the 11 criteria are
present, serially or simultaneously, during any period of observation
Clinical manifestations
• a butterfly rash over the face,
• fever,
• pain but no deformity in one or more peripheral joints (feet, ankles,
knees, hips, fingers, wrists, elbows, shoulders),
• pleuritic chest pain, and
• photosensitivity
Pathology/ morphology
• Heart- Libman sacks endocarditis (more common prior to the
widespread use of steroids)
• Lupus nephritis
• Cutaneous manifestations
• Joints
IMMUNODEFICIENCY STATES
Immunodeficiency
• Primary immunodeficiency
• Inert immunity- defects in leukocyte function, defects in complement system
• Adaptive immunity-
• Di-George syndrome (Thymic hypoplasia
• SCID
• X-linked hypogammaglobulinemia
• Hyper-IgM syndrome
• Specific antibody deficiencies
• Secondary immunodeficiency
Primary immunodeficiencies
• SCID=Severe combined
immunodeficiency- deficiency
in both humoral and cellular
immunity
• X-linked or
• Autosomal recessive
• X-linked agammaglobulinemia
aka Bruton
agammaglobulinemia
• CVID: common variable
immunodeficiency
• ADA=Adenosine deaminase
• Digeorge syndrome- failure of
dev. Of 3rd and 4th pharyngeal
pouches
• Hyper-IgM- Patients make IgM
but deficient in ability to
produce IgG, IgA, IgE
Secondary immunodeficiencies
• Infections including HIV
• Immunonosuppressive therapy
• Malnutrition
• Radiotherapy
• Chemotherapy
HIV
• Prone to infections
• Opportunistic infections
• AIDS-defining illnesses
HIV-associated lymphomas
• Unrestrained proliferation of EBV/ Kaposi sarcoma viruses in infected
cells
• Lymph node Germinal center hyperplasia in early infection with HIV
HIV and HPV
• HIV infected more likely to have persistent HPV
• HPV infected more likely to have HIV
Graft rejection
• Rejection is a process in which T lymphocytes and antibodies
produced against graft antigens react against and destroy tissue grafts
Recognition and Rejection of Transplants
(Allografts)
• The rejection response against solid organ transplants is initiated
mainly by host T cells that recognize the foreign HLA antigens of the
graft, either directly (on APCs in the graft) or indirectly (after uptake
and presentation by host APCs).
Types and mechanisms of rejection of solid
organ grafts:
• Hyperacute rejection. Preformed antidonor antibodies bind to graft
endothelium immediately after transplantation, leading to thrombosis,
ischemic damage, and rapid graft failure.
• Acute cellular rejection. T cells destroy graft parenchyma (and vessels) by
cytotoxicity and inflammatory reactions.
• Acute humoral rejection. Antibodies damage graft vasculature.
• Chronic rejection. Dominated by arteriosclerosis, this type is caused by T-
cell activation and antibodies. The T-cells may secrete cytokines that
induce proliferation of vascular smooth muscle cells, and the antibodies
cause endothelial injury. The vascular lesions and T-cell reactions cause
parenchymal fibrosis
Amyloidosis
• Disorder characterized by the extracellular deposits of misfolded
proteins that aggregate to form insoluble fibrils.
• The deposition of these proteins may result from:
• excessive production of proteins that are prone to misfolding and
aggregation;
• mutations that produce proteins that cannot fold properly and tend to
aggregate;
• defective or incomplete proteolytic degradation of extracellular proteins
Amyloidosis
• Amyloid deposits cause tissue injury and impair normal function by
causing pressure on cells and tissues.
• They do not evoke an inflammatory response.
Amyloidosis
• Systemic or
• localised
Amyloidosis