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🧬 AUTOIMMUNITY

MUHS 2nd MBBS - Pathology (Ref: Robbins & Kumar / Apurb Shastri Oriented)

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DEFINITION

Autoimmunity is the state of adaptive immune responsiveness to self antigens that occurs when mechanisms of self-tolerance fail, resulting in immune-mediated injury to the body's own tissues and organs.

• In other words: The immune system fails to distinguish "self" from "non-self" and mounts an attack against the body's own cells and tissues.
• Robbins & Kumar Basic Pathology

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PART A: FOUR FEATURES OF AUTOIMMUNE DISEASES

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⭐ Feature 1 - Immune Response Against Self Antigens (Autoantibodies / Autoreactive T Cells)

• The hallmark feature: presence of autoantibodies or autoreactive T lymphocytes directed against self antigens
• Examples:
  • Anti-dsDNA, anti-Sm antibodies → SLE
  • Anti-TSH receptor antibodies → Graves' disease
  • Anti-AChR antibodies → Myasthenia gravis
  • Anti-thyroglobulin, anti-TPO → Hashimoto's thyroiditis
  • Autoreactive CD4+/CD8+ T cells → Multiple sclerosis, Type 1 DM

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⭐ Feature 2 - Can Be Organ-Specific OR Systemic

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⭐ Feature 3 - Strong Genetic (HLA) Association

• Most autoimmune diseases are complex multigenic disorders
• Greatest contribution from HLA genes (MHC alleles)

• Genome-wide association studies (GWAS) show polymorphisms in CTLA-4, PTPN22, IL-2 receptor genes in multiple autoimmune diseases

Exam Tip: HLA-B27 + Ankylosing spondylitis is the classic high-yield pairing (odds ratio 100-200)

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⭐ Feature 4 - Female Predominance + Relapsing-Remitting Course

• Many autoimmune diseases show strong female predominance:
  • SLE: Female:Male = 9:1 (reproductive age group 17-55 years)
  • Hashimoto's: 7:1
  • Rheumatoid arthritis: 3:1
  • Multiple sclerosis: 2:1
• Diseases often follow a chronic relapsing-remitting course with periods of flare and remission
• Flares are often triggered by environmental factors (UV radiation in SLE, infections)
• Underlying mechanism of gender bias may involve hormonal effects on immune cells (estrogen promotes immune responses; testosterone suppresses)

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PART B: AUTOIMMUNITY - DEFINITION & MECHANISMS

Self-Tolerance - The Foundation

1. Central tolerance - death (apoptosis/clonal deletion) of immature self-reactive T and B lymphocytes in the thymus and bone marrow; B cells may undergo receptor editing
2. Peripheral tolerance - mature self-reactive lymphocytes are suppressed by:
   • Regulatory T cells (Tregs)
   • Inhibitory receptors (CTLA-4, PD-1)
   • Anergy
   • Apoptosis (Fas-FasL system)

Autoimmunity = Failure of self-tolerance

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OVERVIEW DIAGRAM

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MECHANISMS OF AUTOIMMUNITY

1. Susceptibility genes (influence lymphocyte tolerance)
2. Environmental factors (infections, tissue injury - alter display of and responses to self antigens)

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MECHANISM 1 - Genetic Factors (Susceptibility Genes)

Susceptibility genes
        ↓
Defective tolerance mechanisms
        ↓
Self-reactive lymphocytes escape deletion/suppression
        ↓
Autoimmunity

• HLA genes (most important): Certain MHC alleles present self peptides to T cells in a way that promotes activation rather than tolerance
• Non-MHC genes:
  • FOXP3 mutations → defective Tregs → IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked) - a severe systemic autoimmune disease
  • CTLA-4 polymorphisms → defective inhibitory signaling → T cell overactivation
  • PTPN22 → altered TCR/BCR signaling thresholds
  • IL-2 / IL-2 receptor mutations → impaired Treg maintenance
  • AIRE gene mutations → defective central tolerance (APECED syndrome - Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy)

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MECHANISM 2 - Failure of Central Tolerance (Defective Thymic/Bone Marrow Deletion)

Self-reactive T/B cells normally deleted in
thymus/bone marrow (clonal deletion)
             ↓
FAILURE → Self-reactive lymphocytes escape into periphery
             ↓
Activated by environmental triggers
             ↓
AUTOIMMUNITY

• In thymus: Negative selection eliminates T cells that strongly recognize self-antigens presented by thymic APCs
• Cryptic antigens: Some self-antigens are poorly expressed in thymus (not enough for negative selection), so T cells specific for these "cryptic epitopes" survive into the periphery
• These T cells remain in the repertoire, biased toward weak self-reactivity

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MECHANISM 3 - Failure of Peripheral Tolerance

3a. Loss of Regulatory T cells (Tregs)

• CD4+ FOXP3+ CD25+ Tregs normally suppress self-reactive lymphocytes
• Suppress via: IL-10, TGF-β secretion; CTLA-4 expression (blocks B7-CD28 costimulation)
• FOXP3 mutations → absent Tregs → severe multi-organ autoimmunity (IPEX)

3b. Failure of Anergy (Clonal Anergy)

• Normally: T cell recognizing self-antigen WITHOUT costimulation (no B7-CD28 signal) becomes anergic (functionally unresponsive)
• If infections/inflammation upregulate B7 (costimulatory molecules) on APCs, this anergy is broken → self-reactive T cells become activated

3c. Defective Apoptosis (Fas-FasL System)

• Self-reactive T cells normally express Fas (CD95) upon encountering self-antigen → FasL on activated T cells engages Fas → apoptosis
• Mutations in Fas or FasL → lymphocytes accumulate → ALPS (Autoimmune Lymphoproliferative Syndrome) - resembles lupus

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MECHANISM 4 - Molecular Mimicry (Infection-Triggered)

Microbe with antigen similar to self-antigen
              ↓
Immune response generated against microbe
              ↓
Cross-reactive antibodies/T cells produced
              ↓
Attack self-tissue (cross-reaction = molecular mimicry)
              ↓
AUTOIMMUNITY

• Rheumatic Heart Disease: Antibodies produced against Group A Streptococcus cross-react with cardiac antigens (M-protein vs. cardiac myosin)
• Campylobacter jejuni (Penner O:19 serotype) → GD1b ganglioside cross-reaction → Guillain-Barre Syndrome / Axonal neuropathy
• Coxsackievirus → beta-cell antigens → Type 1 Diabetes (proposed)

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MECHANISM 5 - Breakdown of Anergy by Infection / Induction of Costimulators on APCs

• A) Induction of costimulators on APCs: Microbes activate APCs via pattern recognition (TLRs), inducing B7 expression. Self-reactive T cells that were anergic (because APCs lacked costimulators before) now receive the second (costimulatory) signal → become activated → autoimmunity
• B) Molecular mimicry: As described above

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MECHANISM 6 - Release of Sequestered (Hidden) Antigens

Certain self-antigens are normally hidden from immune system
(eye - lens protein, testis - sperm antigens, brain - myelin)
              ↓
These antigens are not present in thymus for negative selection
              ↓
Self-reactive T/B cells for these antigens survive normally
              ↓
TRAUMA / INFECTION / TISSUE INJURY
releases sequestered antigens
              ↓
These antigens now encounter self-reactive lymphocytes
              ↓
AUTOIMMUNITY

• Post-traumatic uveitis / Sympathetic ophthalmia: Injury to one eye releases lens proteins; immune response damages the other uninjured eye
• Post-vasectomy orchitis: Sperm antigens released → anti-sperm antibodies
• Post-myocardial infarction pericarditis (Dressler syndrome): Cardiac antigens released

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MECHANISM 7 - Epitope Spreading

Autoimmune disease starts, targeting ONE antigen
              ↓
Tissue injury releases additional self-antigens
              ↓
These new antigens are picked up and presented by APCs
              ↓
New, broader autoimmune responses generated against
previously unrecognized ("cryptic") epitopes
              ↓
EPITOPE SPREADING → disease worsens / perpetuates

• Spreading of autoimmune reaction from one antigen to another = determinant spreading / epitope spreading
• Important in perpetuation of autoimmune disease
• Example: In SLE, initial response to dsDNA → spreads to histones, Sm antigen, SSA, SSB, etc.
• Example: MS - initial response to one myelin protein epitope → spreads to multiple myelin antigens

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MECHANISM 8 - Polyclonal Lymphocyte Activation (Superantigens / Bystander Activation)

• Certain microbes (esp. bacteria with superantigens) activate large numbers of T cells non-specifically by binding outside the antigen-binding groove of MHC-TCR
• This polyclonal activation can activate self-reactive T cells that would otherwise remain quiescent (bystander activation)
• Example: Staphylococcal TSST-1 (toxic shock syndrome toxin), Streptococcal M protein act as superantigens

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MECHANISM 9 - Abnormal Display of Self Antigens / Neoantigen Formation

• Posttranslational modifications can create new epitopes (neoantigens) to which the immune system is not tolerant:
  • Citrullination of proteins (conversion of arginine to citrulline by PAD4 enzyme) → anti-citrullinated protein antibodies (ACPA/anti-CCP) → Rheumatoid Arthritis
  • UV irradiation → cell death → nuclear antigen exposure → SLE flares
  • Smoking → chemical modification of self antigens → RA risk
  • Apoptotic cells not cleared efficiently → persistent nuclear antigen exposure → SLE

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SUMMARY TABLE: Mechanisms of Autoimmunity

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EXAM MEMORY TRICKS (MUHS-Oriented)

"GSE-FARM-PE" for Mechanisms:

• Genetic susceptibility
• Sequestered antigen release
• Epitope spreading
• Failure of central tolerance
• Anergy failure (costimulator induction)
• Regulatory T cell defect
• Molecular mimicry
• Polyclonal activation (superantigens)
• Environmental triggers (UV, smoking, infections)

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Four Features of Autoimmune Diseases (Memory: "I-GFC"):

1. Immune response against self (autoantibodies / autoreactive T cells)
2. Genetic (HLA) association
3. Female predominance + relapsing-remitting course
4. Can be organ-specific OR systemic

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IMPORTANT MUHS EXAM POINTS ⭐

1. SLE - prototype systemic autoimmune disease; anti-dsDNA + anti-Sm = diagnostic; female:male = 9:1; lupus nephritis by immune complex deposition
2. FOXP3 mutation → IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked) - the classic Treg defect causing autoimmunity
3. ALPS (Autoimmune Lymphoproliferative Syndrome) = Fas/FasL mutation → resembles lupus
4. Molecular mimicry classic = Rheumatic heart disease (Group A Strep → cross-reacts with cardiac myosin)
5. HLA-B27 has odds ratio of 100-200 for Ankylosing Spondylitis (highest)
6. AIRE gene in thymus controls central tolerance for peripheral antigens; AIRE mutation → APECED
7. Citrullination of proteins → Anti-CCP antibodies = highly specific for RA
8. Sympathetic ophthalmia = classic sequestered antigen example
9. Autoimmunity results from: Susceptibility genes + Environmental triggers (the two-hit model)
10. Regulatory T cells: CD4+, CD25+ (high), FOXP3+ - suppress via IL-10, TGF-β, CTLA-4

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🦠 AUTOIMMUNITY

MUHS 2nd MBBS - Microbiology (Immunology Section)

Ref: Ananthanarayan & Paniker | Apurb Shastri | Jawetz Medical Microbiology

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DEFINITION OF AUTOIMMUNITY

Autoimmunity is defined as the failure of self-tolerance, in which the immune system generates antibodies (autoantibodies) or T lymphocytes directed against the body's own (self) antigens, leading to tissue damage.

• Self-tolerance = the normal state in which the immune system does not react against self-antigens
• When self-tolerance breaks down → Autoimmune disease
• The immune responses that cause self-tissue injury are called autoimmune responses

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DEFINITION OF AUTOIMMUNE DISEASE

Autoimmune disease is a condition in which structural or functional damage is produced by the action of immunologically competent cells or antibodies against the normal components of the body.

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FOUR FEATURES OF AUTOIMMUNE DISEASES

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⭐ FEATURE 1 - Presence of Autoantibodies or Autoreactive T Cells

• The hallmark of autoimmunity
• Autoantibodies are immunoglobulins directed against self antigens
• In some diseases, autoreactive T cells (CD4+/CD8+) attack self tissues directly

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⭐ FEATURE 2 - Genetic (HLA) Association

• Strong association with HLA (MHC) alleles
• Certain HLA alleles present self-peptides to T cells in a way that favours activation over tolerance

Exam Tip: HLA-B27 and Ankylosing Spondylitis = highest relative risk in all autoimmune diseases

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⭐ FEATURE 3 - Female Predominance

• Most autoimmune diseases show female preponderance
• Attributed to: Hormonal factors (estrogen promotes immune activation), X-chromosome effects (immune genes on X chromosome)

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⭐ FEATURE 4 - Can Be Organ-Specific OR Non-Organ Specific (Systemic)

AUTOIMMUNE DISEASES
        |
   _____|_____
  |           |
ORGAN        SYSTEMIC
SPECIFIC     (Non-organ specific)
  |              |
Hashimoto's    SLE
Graves'        RA
MG             Systemic Sclerosis
Type 1 DM      Sjögren Syndrome
Goodpasture's  MCTD

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MECHANISMS OF AUTOIMMUNITY

The fundamental cause = BREAKDOWN OF SELF-TOLERANCE

How is Self-Tolerance Normally Maintained?

                SELF-TOLERANCE
                      |
         _____________|_____________
        |                           |
CENTRAL TOLERANCE            PERIPHERAL TOLERANCE
(Thymus / Bone marrow)       (Peripheral lymphoid organs)
        |                           |
Clonal deletion of          Anergy, Treg suppression,
self-reactive T/B cells     Apoptosis (Fas-FasL)

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MECHANISM 1: FAILURE OF CLONAL DELETION (Central Tolerance Failure)

Thymus normally deletes T cells reactive to self antigens
(Negative selection - requires AIRE gene)
              ↓
FAILURE:
• Weak self antigens ("cryptic") not expressed in thymus
• AIRE gene mutation → peripheral antigens not displayed in thymus
              ↓
Self-reactive T cells escape into periphery
              ↓
Triggered by infections/injury → AUTOIMMUNITY

• AIRE (Autoimmune Regulator) gene: Controls expression of peripheral self-antigens in the thymus for negative selection
• AIRE mutation → APECED syndrome (Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy)

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MECHANISM 2: FAILURE OF PERIPHERAL TOLERANCE

a) Loss of Regulatory T Cells (Tregs)

Tregs (CD4+, CD25+, FOXP3+) 
normally suppress self-reactive lymphocytes
via IL-10, TGF-β, CTLA-4
              ↓
FOXP3 gene mutation → Tregs absent
              ↓
IPEX syndrome (Immune dysregulation,
Polyendocrinopathy, Enteropathy, X-linked)
= severe multi-organ autoimmunity

b) Anergy Failure (Costimulation Bypass)

Normally:
T cell + self antigen WITHOUT costimulation → ANERGY

Infection/inflammation upregulates B7 on APCs
              ↓
Costimulation (B7-CD28) now provided
              ↓
Previously anergic self-reactive T cells ACTIVATED
              ↓
AUTOIMMUNITY

c) Failure of Apoptosis (Fas-FasL Defect)

Self-reactive T cells normally undergo apoptosis
via Fas (CD95) - FasL interaction
              ↓
FAS or FAS LIGAND MUTATION
              ↓
Self-reactive lymphocytes accumulate
              ↓
ALPS (Autoimmune Lymphoproliferative Syndrome)
(resembles lupus)

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MECHANISM 3: MOLECULAR MIMICRY ⭐

Definition: A microbial antigen shares structural similarity with a self-antigen. The immune response generated against the microbe cross-reacts with the self-antigen → autoimmune tissue damage.

INFECTION with microbe
      ↓
Microbe antigen resembles self-antigen (structural similarity)
      ↓
Immune response to microbe → antibodies + T cells
      ↓
These cross-react with self-tissue
      ↓
AUTOIMMUNE DAMAGE

MUHS Exam: Rheumatic Heart Disease = MOST IMPORTANT example of molecular mimicry. Always write this first!

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MECHANISM 4: RELEASE OF SEQUESTERED (HIDDEN) ANTIGENS

Certain self-antigens are normally anatomically hidden (sequestered) from the immune system. They are not present in the thymus, so no tolerance is developed. When released by trauma/infection, they trigger an autoimmune response.

Sequestered antigens:
• Lens of eye (lens protein)
• Sperm antigens (testis)
• Myelin antigens (CNS - blood-brain barrier)
• Cardiac antigens (released after MI)
              ↓
TRAUMA / SURGERY / INFECTION
              ↓
Sequestered antigens released into circulation
              ↓
Encountered by self-reactive lymphocytes
(which were never deleted because antigen was never seen)
              ↓
AUTOIMMUNE RESPONSE

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MECHANISM 5: POLYCLONAL LYMPHOCYTE ACTIVATION (Superantigens)

Superantigens are microbial proteins that activate large numbers of T cells non-specifically by binding outside the antigen-binding groove of the MHC-TCR complex.

Normal antigen: activates ~1 in 10,000 T cells (antigen-specific)
Superantigen: activates up to 20% of all T cells (non-specific)
              ↓
Massive polyclonal T cell activation
              ↓
Includes activation of self-reactive T cells (bystander activation)
              ↓
AUTOIMMUNITY

• Staphylococcal TSST-1 (Toxic Shock Syndrome Toxin-1)
• Staphylococcal Enterotoxins A, B, C
• Streptococcal Pyrogenic Exotoxins (SPE A, C)

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MECHANISM 6: EPITOPE SPREADING

As autoimmune disease progresses, tissue damage releases additional self-antigens. These expose new ("cryptic") epitopes to the immune system → new autoimmune responses are generated against previously unrecognized self-epitopes. This perpetuates and worsens the disease.

Initial autoimmune response to ONE self-antigen (dominant epitope)
              ↓
Tissue damage releases more self-antigens
              ↓
Cryptic (hidden) epitopes now exposed and presented
              ↓
New autoimmune responses to NEW antigens
              ↓
DISEASE PERPETUATION AND SPREADING

• Example: SLE - starts with anti-dsDNA → spreads to anti-histone, anti-Sm, anti-SSA, anti-SSB
• Example: MS - one myelin epitope → spreads to multiple myelin antigens

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MECHANISM 7: NEOANTIGEN FORMATION (Post-translational Modifications)

• Normally, these modified forms of self-proteins are not expressed → no tolerance exists for them
• Citrullination: Enzyme PAD4 converts arginine → citrulline in proteins → anti-CCP antibodies in RA
• UV radiation: Causes cell death → nuclear antigens released → SLE flares
• Smoking: Chemical modification of self-proteins → RA susceptibility

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COMPLETE SUMMARY DIAGRAM

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MECHANISMS - QUICK REVISION TABLE

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⭐ HIGH-YIELD MUHS EXAM POINTS

1. Definition: Failure of self-tolerance → immune attack on self-antigens
2. Four Features: Autoantibodies, HLA association, Female predominance, Organ-specific vs Systemic
3. Molecular mimicry = most important mechanism for Microbiology exam - Rheumatic heart disease (Strep) is the MUST-WRITE example
4. Sympathetic ophthalmia = sequestered antigen (lens protein)
5. Dressler syndrome = sequestered antigen (cardiac antigen post-MI)
6. FOXP3 mutation → IPEX; AIRE mutation → APECED; FAS mutation → ALPS
7. Superantigens activate up to 20% of all T cells (vs 0.01% for normal antigens)
8. Anti-dsDNA + Anti-Sm = diagnostic of SLE
9. HLA-B27 = highest relative risk (100-200x) → Ankylosing spondylitis
10. SLE female:male = 9:1 - always write this ratio

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MEMORY AIDS

"4 Features = IGFS"

• I = Immune response against self (autoantibodies/autoreactive T cells)
• G = Genetic (HLA) association
• F = Female predominance
• S = Systemic OR organ-specific

Mechanisms = "FSMSPEN"

• F = Failure of central tolerance
• S = Sequestered antigen release
• M = Molecular mimicry
• S = Superantigen (polyclonal activation)
• P = Peripheral tolerance failure (Tregs, Anergy, Apoptosis)
• E = Epitope spreading
• N = Neoantigen formation

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