Autoimmunity and the Adaptive Immune Response: Comprehensive Study Guide

Introduction to Autoimmunity and the Disruption of Healthy Tissue

• Autoimmune disease occurs as a result of the failure of mechanisms that maintain self-tolerance.

  • can’t distinguish self from non self

  • loss of tolerance

• Both antibody and effector T cells are actively involved in the autoimmune process.

• The sequence involves an autoantigen triggering an autoimmune response, which leads to autoimmunity.

• Comparison of Immune Systems: Innate immunity is inherently better at distinguishing between self and non-self than adaptive immunity. However, adaptive immunity possesses several specific mechanisms designed to eliminate or inhibit cells that express receptors reactive to self-antigens.

Classification of Autoimmune Diseases by Hypersensitivity Resemblance

• Every autoimmune disease resembles a type II, III, or IV hypersensitivity reaction.

  • antibodies involved depending which hypersensitivity it resembles

    • IgE, IgG

  • 
    

Type II Hypersensitivity Resemblance

• Mechanism: Antibodies directed against cell-surface or matrix antigens.

• Examples and Consequences:

  • Autoimmune hemolytic anemia: Antigens involved are Rh blood group antigens and I antigen. The consequence is the destruction of red blood cells by complement and phagocytes, leading to anemia.

  • Autoimmune thrombocytopenia purpura: Antigen is the platelet integrin $gpIIb:IIIa$. The consequence is abnormal bleeding.

  • Goodpasture's syndrome: Antigen is the non-collagenous domain of basement membrane collagen type IV. Consequence involves Glomerulonephritis and pulmonary hemorrhage.

  • Pemphigus vulgaris: Antigen is epidermal cadherin. Consequence is blistering of the skin.

  • Pemphigus foliaceus: Antigen is desmoglein. Consequence is mild blistering of the skin.

  • Acute rheumatic fever: Antigens are Streptococcal cell wall antigens. Antibodies cross-react with cardiac muscle, leading to arthritis, myocarditis, and late scarring of heart valves.

  • Graves' disease: The antigen is the Thyroid-stimulating hormone (TSH) receptor. The consequence is Hyperthyroidism.

    • thyroid sets up metabollic activity, too much tr too little results in

  • Myasthenia gravis: Antigen is the Acetylcholine receptor. Consequence is progressive weakness.

  • Type 2 diabetes (insulin-resistant diabetes): Antigen is the Insulin receptor (acting as an antagonist). Consequence is Hyperglycemia and ketoacidosis.

  • Hypoglycemia: Antigen is the Insulin receptor (acting as an agonist). Consequence is Hypoglycemia.

Type III Hypersensitivity Resemblance (Immune-complex disease)

• Mechanism: Formation of immune complexes that deposit in tissues.

• Examples and Consequences:

  • Subacute bacterial endocarditis: Antigen is bacterial antigen. Consequence is Glomerulonephritis.

  • Mixed essential cryoglobulinemia: Antigen is Rheumatoid factor IgG complexes (with or without hepatitis C antigens). Consequence is systemic vasculitis.

  • Systemic lupus erythematosus (SLE): Antigens include DNA, histones, ribosomes, snRNP, and scRNP. Consequences are Glomerulonephritis, vasculitis, and arthritis.

Type IV Hypersensitivity Resemblance (T cell-mediated disease)

• Mechanism: Effector T cells causing tissue damage.

• Examples and Consequences:

  • Type 1 diabetes (insulin-dependent diabetes mellitus): Antigen is Pancreatic $\beta$-cell antigen. Consequence is $\beta$-cell destruction.

  • Rheumatoid arthritis: Antigen is an unknown synovial joint antigen. Consequence is joint inflammation and destruction.

  • Multiple sclerosis: Antigens are Myelin basic protein and proteolipid protein. Consequence is brain degeneration and paralysis.

Mechanisms of Self-Tolerance and Loss of Tolerance

• Autoimmune diseases arise specifically when tolerance to self-antigens is lost.

• Primary mechanisms contributing to immunological self-tolerance include:

  • Negative selection of B cells in the bone marrow.

    • B cells recognize self antigen, induced apoptosis

  • Expression of tissue-specific proteins in the thymus (facilitated by AIRE) so they participate in the negative selection of T cells.

  • Negative selection of T cells in the thymus.

  • Exclusion of lymphocytes from certain peripheral tissues (immunologically privileged sites): brain, eye, and testis.

  • Induction of anergy in autoreactive B and T cells that reach the peripheral circulation.

  • Suppression of autoimmune responses by regulatory T cells (Tregs).

The Role of AIRE

• Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by a lack of AIRE.

• This condition provides compelling evidence for the fundamental connection between immunological tolerance and the prevention of autoimmunity.

  • AIRE not able to produce self antigen for T cells to recognize, which leads to the survival of autoreactive T cells and ultimately results in the breakdown of self-tolerance.

  • can attack body’s own tissue and lead to autoimmune dieases

Genetic and Environmental Factors in Autoimmunity

• HLA (Human Leukocyte Antigen) is the dominant genetic factor affecting susceptibility to autoimmune disease.

HLA-Associated Risk Factors

• Sibling analysis: Of all sibling pairs with diabetes, $58\%$ share 2 HLA haplotypes, $37\%$ share 1 HLA haplotype, and only $5\%$ share 0 HLA haplotypes.

• Relative risks for specific HLA allotypes:

  • Ankylosing spondylitis: HLA-B27; Relative risk > $150$.

  • Birdshot chorioretinopathy: HLA-A29; Relative risk > $50$.

  • Narcolepsy: HLA-DQ6; Relative risk > $40$.

  • Celiac disease: HLA-DQ2 and DQ8; Relative risk $30$.

  • Type 1 diabetes: HLA-DQ2 and DQ8; Relative risk $14$.

  • Subacute thyroiditis: HLA-B35; Relative risk $14$.

  • Multiple sclerosis: HLA-DQ6; Relative risk $12$.

  • Rheumatoid arthritis: HLA-DR4; Relative risk $9$.

  • Juvenile rheumatoid arthritis: HLA-DR8; Relative risk $8$.

  • Psoriasis vulgaris: HLA-Cw6; Relative risk $7$.

  • Addison's disease: HLA-DR3; Relative risk $5$.

  • Graves' disease: HLA-DR3; Relative risk $4$.

  • Myasthenia gravis: HLA-DR3; Relative risk $2$.

  • Type 1 diabetes (protective): HLA-DQ6; Relative risk < $0.02$.

Sex-Based and Population Differences

• Women generally utilize a Th-1 response, while men utilize a Th-2 response.

• Consequently, women are more resistant to infections but suffer more frequently from antibody-mediated autoimmune diseases.

• Estrogen enhances adaptive immunity, whereas Testosterone is immunosuppressive.

  • Estrogen is a very inflammatory hormone that will increase an adaptive response

• Autoimmune diseases are more prevalent in Caucasians than in other populations.

• Many autoimmune diseases are associated with CD4 helper T cells, suggesting these cells are more likely to lose tolerance.

• Inflamed cells increase their expression of MHC, further promoting the autoimmune cycle.

Antibody-Mediated Autoimmune Pathologies

• Binding of antibodies to cell-surface receptors is a primary cause of several diseases.

Antibody-Receptor Interaction Syndromes

• Graves' disease: Anti-TSH receptor antibody acts as an agonist. Target is thyroid epithelial cells. This results in hyperthyroidism and the overproduction of thyroid hormones. Symptoms include heat intolerance, nervousness, irritability, warm moist skin, weight loss, and an enlarged thyroid.

• Myasthenia gravis: Anti-Acetylcholine receptor antibody acts as an antagonist. Target is muscle cells. This leads to progressive muscle weakening.

• Insulin-resistant diabetes: Anti-Insulin receptor antibody acts as an antagonist. Targets all cells. Results in hyperglycemia and ketoacidosis.

• Hypoglycemia: Anti-Insulin receptor antibody acts as an agonist. Targets all cells. Results in low blood sugar levels.

Experimental Validation

• The transfer of autoimmune serum to a healthy recipient should cause the same disease. For example, serum from a Graves' disease patient injected into mice caused them to overproduce thyroid hormone.

Inflammation and Organized Lymphoid Tissue

• Organized lymphoid tissue (tertiary lymphoid organs) sometimes forms at sites inflamed by autoimmune disease.

• Hashimoto's thyroiditis: The infiltrated thyroid develops structures resembling secondary lymphoid tissue. It is caused by a CD4 Th1 response. Peripheral lymphocytes infiltrate the thyroid, leading to progressive destruction until the patient is unable to produce thyroid hormone (hypothyroidism).

• Vulnerability of Endocrine Glands: Endocrine glands are prone to autoimmunity because they produce tissue-specific proteins not expressed elsewhere and they are well-vascularized, facilitating interactions with the immune system.

Epitope Spreading in Autoimmune Disease

• Epitope spreading occurs when the antibody response to an autoantigen broadens and strengthens over time.

Intramolecular Epitope Spreading (Pemphigus foliaceus)

• The autoantigen is desmoglein.

• Early, non-pathological IgG is made against the EC5 domain.

• Later, the response spreads to EC1 and EC2 domains.

• Pathological IgG4 antibodies made against EC1 and EC2 "unzip" the adhesive interactions of desmoglein between keratinocytes, causes blistering.

Intermolecular Epitope Spreading (Systemic Lupus Erythematosus - SLE)

• SLE leads to cellular components becoming antigens through both intramolecular and intermolecular spreading.

• Specific HLA-Autoantibody associations in SLE:

  • HLA-DR3: Antibodies to cytoplasmic ribonucleoprotein.

  • HLA-DR2: Antibodies to double-stranded DNA (dsDNA).

  • HLA-DR5: Antibodies to the spliceosome.

• Clinical features of SLE: Named "Lupus" (Latin for wolf), characterized by a butterfly-shaped erythema (rash). It is systemic, eventually causing death via organ failure. Diagnosis uses Anti-nuclear antibodies (ANA). There is no cure; only immunosuppression is available.

Therapeutic Interventions

Intravenous Immunoglobulin (IVIG) Therapy

• IVIG is beneficial for Grave's ophthalmopathy (bulging eyes), immune thrombocytopenia, dermatomyositis, autoimmune uveitis, and potentially SLE, RA, and Type 1 diabetes.

• Mechanisms of IVIG Action:

  • Saturates Fc receptors and inhibits Fc receptor-mediated phagocytosis.

  • Saturates FcRn, inhibiting the recycling of IgG, which increases IgG clearance and reduces its half-life in the blood.

  • Upregulates expression of inhibitory $Fc\gamma RIIB$ to further inhibit phagocytosis.

  • Contains anti-idiotypic antibodies that neutralize the patient's autoantibodies.

  • Suppresses the patient's eigene immunoglobulin and autoantibody production.

  • Contains helpful autoantibodies (e.g., anti-BAFF) that prevent B-cell survival.

  • Downregulates antigen presentation.

  • Attenuates complement activation.

Monoclonal Antibodies for Rheumatoid Arthritis (RA)

• RA involves chronic inflammation and joint destruction.

• Rheumatoid Factor (RF): Anti-immunoglobulin antibodies (IgM, IgG, or IgA) produced against the patient's own IgG.

• Cell types in RA joints:

  • Plasma cells: Produce RF.

  • CD4 T cells: Activate macrophages to produce pro-inflammatory cytokines: $TNF\alpha$, $IL-1$, $IL-6$, and $IL-7$.

  • Inflammatory cells: Produce prostaglandins and leukotrienes.

  • Neutrophils: Release lysosomal enzymes.

• Anti-$TNF\alpha$ therapy: Significantly reduces C-reactive protein (CRP) levels, swollen-joint counts, and subjective pain scores compared to placebo.

Genetic and Environmental Factors in Rheumatoid Arthritis

• RA is influenced by specific $DRB1*04$ alleles (amino acid positions 67, 70, and 71 in the $DR\beta$ chain).

• Periodontitis connection: The bacterium Porphyromonas gingivalis produces Peptidyl arginine deaminase (PPAD), which differs from human PAD. PPAD-mediated citrullinated proteins lead to a loss of T cell tolerance.

• Thymus Involution: As the thymus shrinks with age, naive T cells are not produced. Remaining T cells proliferate, become refractory to apoptosis, lose CD28 expression, and begin expressing NK-cell receptors.

Infection-Induced Autoimmunity (Molecular Mimicry)

• Autoimmune disease can be an adverse side-effect of an immune response to infection.

• Rheumatic Fever: Streptococcus cell wall stimulates antibodies that cross-react with heart tissue.

• Infection/HLA/Autoimmune Associations:

  • Chlamydia trachomatis / HLA-B27: Reiter's syndrome (arthritis).

  • Shigella, Salmonella, Yersinia, Campylobacter / HLA-B27: Reactive arthritis.

  • Borrelia burgdorferi / HLA-DR2, DR4: Chronic arthritis in Lyme disease.

  • Coxsackie virus, Rubella / HLA-DQ2, DQ8, DR4: Type 1 diabetes.

Noninfectious Environmental Factors

• Sympathetic ophthalmia: Trauma to one eye releases sequestered intraocular protein antigens. These antigens travel to lymph nodes, activate T cells, and the resulting effector T cells attack both the injured and the healthy eye via the bloodstream.