Histocompatibility: 3.
Importance of MHC Restriction in Immune Responses
STRUCTURE OF MHC :
1. Structure of MHC Class I Antigen
 MHC Class I molecules consist of two polypeptide chains: an alpha chain and a
beta-2 microglobulin chain.
 The alpha chain has three domains: α1, α2, and α3. The α1 and α2 domains
form the peptide-binding groove.
Mode of Antigen Preparation for MHC Class I
 Peptides from cytoplasmic proteins are processed and loaded onto MHC Class I
molecules.
 This process involves proteasomal degradation of intracellular proteins,
followed by transport of peptide fragments into the endoplasmic reticulum
where they bind to MHC Class I molecules.
2. Structure of MHC Class II Antigen
 MHC Class II molecules consist of two chains: an alpha chain and a beta chain,
each with two domains: α1 and α2, and β1 and β2, respectively.
 The peptide-binding groove is formed by the α1 and β1 domains.
4. Mode of Antigen Preparation for MHC Class II
 Peptides from extracellular proteins are processed and loaded onto MHC Class
II molecules.
 This process involves endocytosis of extracellular proteins into antigen-
presenting cells, where they are degraded in lysosomes and the resulting
peptide fragments bind to MHC Class II molecules within endosomes or
lysosomes.
5. Structure of MHC Class III Antigen and Role
 MHC Class III molecules include components of the complement system,
cytokines, and other proteins involved in immune responses.
 They are not directly involved in antigen presentation like Class I and II.
MHC RESTRICTION
1. Definition of MHC Restriction
 MHC (Major Histocompatibility Complex) restriction refers to the specificity of T
cell recognition of antigenic peptides presented by MHC molecules.
 T cells recognize antigens only when presented in association with self-MHC
molecules.
2. Role of MHC Restriction in T Cell Activation
 MHC restriction ensures that T cells recognize only foreign antigens presented
by self-MHC molecules.
 T cell receptor (TCR) engagement with antigen-MHC complex initiates T cell
activation and immune response.
 MHC restriction ensures that T cells respond appropriately to pathogens while
avoiding self-reactivity.
 It contributes to the specificity and effectiveness of the adaptive immune
response.
4. Experimental Evidence of MHC Restriction
 Studies using T cell clones and hybridomas have demonstrated that T cells
recognize antigens only when presented by MHC molecules of the same
individual or species.
 Transgenic animal models expressing foreign MHC molecules have shown
altered T cell recognition patterns.
5. Implications of MHC Restriction in Transplantation and Autoimmunity
 Mismatch of MHC molecules between donor and recipient leads to rejection of
transplanted tissues.
 Autoimmune diseases arise from breakdown of self-tolerance, where T cells
recognize self-antigens presented by self-MHC molecules.
COMPLEMENT SYSTEM :
1. Components of the Complement System
 Complement proteins are part of the innate immune system and consist of over
30 proteins circulating in the blood and found on cell surfaces.
 Key components include complement proteins C1 through C9, complement
regulatory proteins (e.g., Factor H), and complement receptors on cell surfaces.
2. Classical Pathway of Complement Activation
 Initiated by binding of complement protein C1 to antigen-antibody complexes
(immune complexes) on pathogen surfaces.
 Activation of C1 leads to sequential activation of complement proteins C4 and C2,
forming the classical pathway C3 convertase (C4b2a).
 C3 convertase cleaves complement protein C3 into C3a and C3b, leading to
opsonization, inflammation, and membrane attack complex (MAC) formation.
3. Alternative Pathway of Complement Activation
 Initiated spontaneously by hydrolysis of complement protein C3 in the absence of
specific antibodies.
 C3b binds to pathogen surfaces directly or through interactions with certain
molecules (e.g., bacterial lipopolysaccharides), forming the alternative pathway
C3 convertase (C3bBb).
 Similar to the classical pathway, activation of C3 leads to opsonization,
inflammation, and MAC formation.
HYPERSENSITIVITY :
1. Definition of Hypersensitivity
- Hypersensitivity refers to exaggerated or inappropriate immune responses to
harmless antigens, leading to tissue damage or disease.
2. Classification of Hypersensitivity Reactions
- Hypersensitivity reactions are classified into four types based on immune
mechanisms: Type I, Type II, Type III, and Type IV.
 Type I: Immediate hypersensitivity mediated by IgE antibodies.
 Type II: Antibody-mediated hypersensitivity involving complement activation and
destruction of cells or tissues.
 Type III: Immune complex-mediated hypersensitivity causing inflammation and
tissue damage.
 Type IV: Delayed-type hypersensitivity mediated by T cells, leading to cell-
mediated immune reactions.
3. Examples of Hypersensitivity Disorders
 Type I: Allergic rhinitis, asthma, anaphylaxis.
 Type II: Autoimmune hemolytic anemia, Graves' disease.
 Type III: Systemic lupus erythematosus (SLE), rheumatoid arthritis.
 Type IV: Contact dermatitis, tuberculin skin test reaction.
4. Mechanisms of Hypersensitivity Reactions
- Type I: Antigen cross-linking of IgE bound to mast cells and basophils triggers
release of inflammatory mediators like histamine.
- Type II: Antibody-mediated cytotoxicity or complement activation leads to cell or
tissue damage.
- Type III: Formation of immune complexes activates complement and recruits
inflammatory cells, causing tissue damage.
- Type IV: Sensitized T cells release cytokines upon exposure to antigens, leading to
inflammation and tissue injury.
5. Clinical Management of Hypersensitivity Disorders
- Treatment strategies include allergen avoidance, pharmacotherapy (e.g.,
antihistamines, corticosteroids), desensitization therapy, and immunomodulatory
agents.
- Severe hypersensitivity reactions may require emergency interventions like
epinephrine administration and supportive care.
AUTOIMMUNITY :
1. Definition of Autoimmunity
- Autoimmunity refers to an immune response against self-antigens, where the
immune system mistakenly recognizes and attacks the body's own tissues.
2. Mechanisms of Autoimmunity
- Breakdown of self-tolerance mechanisms allows autoreactive lymphocytes to
evade elimination in the thymus or bone marrow.
- Various factors contribute to autoimmunity, including genetic predisposition,
environmental triggers, and dysregulation of immune checkpoints.
3. Examples of Autoimmune Diseases
- Rheumatoid arthritis: Autoimmune inflammation of joints, leading to pain,
swelling, and joint damage.
- Type 1 diabetes mellitus: Autoimmune destruction of insulin-producing beta cells
in the pancreas, causing hyperglycemia.
- Multiple sclerosis: Autoimmune attack on myelin sheath of nerves, resulting in
neurological symptoms.
- Systemic lupus erythematosus (SLE): Autoimmune disorder affecting multiple
organs, characterized by inflammation and autoantibody production.
4. Diagnostic Approaches for Autoimmune Diseases
- Clinical evaluation: Assessment of symptoms, physical examination, and medical
history.
- Laboratory tests: Detection of autoantibodies (e.g., antinuclear antibodies,
rheumatoid factor), inflammatory markers, and imaging studies.
- Biopsy: Examination of tissue samples to confirm autoimmune pathology.
5. Treatment Strategies for Autoimmune Diseases
- Immunosuppressive therapy: Drugs that suppress immune activity to reduce
inflammation and tissue damage (e.g., corticosteroids, methotrexate).
- Biologic agents: Targeted therapies that inhibit specific immune pathways or
cytokines involved in autoimmune processes (e.g., TNF-alpha inhibitors, interleukin-6
inhibitors).
- Disease-modifying antirheumatic drugs (DMARDs): Medications that slow disease
progression and preserve joint function in rheumatic conditions.