Immunodeficiency: Definition, Classification & Clinical Importance

 

Immunodeficiency: Definition, Classification & Clinical Importance

Definition

Immunodeficiency refers to a state of impaired immune function, leading to an increased susceptibility to infections, autoimmune diseases, and malignancies. It results from defects in the immune system, affecting innate or adaptive immunity. Immunodeficiencies can be congenital (genetic) or acquired due to external factors such as infections, malignancies, or immunosuppressive therapy.

---

Classification of Immunodeficiency

1. Primary Immunodeficiency (PID) [Congenital, due to genetic defects]

• Cause: Mutations in genes regulating immune function, leading to defective immune cell development or function.
• Onset: Usually presents in infancy or early childhood.
• Pathophysiology: Defects in lymphocyte development, phagocytic function, or complement activation result in recurrent and severe infections.
• Examples:
  • Severe Combined Immunodeficiency (SCID)
    • Defect: Mutations in IL2RG (X-linked) or ADA deficiency (autosomal recessive) lead to a lack of functional B and T cells.
    • Clinical Importance: Infants present with recurrent bacterial, viral, fungal, and opportunistic infections. Without early intervention (bone marrow transplant), death occurs within the first year.
  • Bruton’s X-linked Agammaglobulinemia
    • Defect: Mutation in BTK gene prevents B-cell maturation, leading to absent immunoglobulin production.
    • Clinical Importance: Recurrent bacterial infections (e.g., pneumonia, otitis media) due to lack of antibody-mediated immunity.

2. Secondary (Acquired) Immunodeficiency [Develops later due to external factors]

• Cause: Chronic diseases, infections, malignancies, or immunosuppressive drugs.
• Onset: Can occur at any age depending on the cause.
• Pathophysiology: Progressive depletion or suppression of immune cells leads to immune system failure.
• Examples:
  • HIV/AIDS (Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome)
    • Defect: HIV infects CD4+ T cells, leading to progressive T-cell depletion and immune dysfunction.
    • Clinical Importance: Increased susceptibility to opportunistic infections (e.g., Pneumocystis jirovecii pneumonia, tuberculosis) and AIDS-defining malignancies (Kaposi sarcoma, non-Hodgkin lymphoma).
  • Chemotherapy-Induced Immunosuppression
    • Defect: Cytotoxic drugs destroy rapidly dividing cells, including hematopoietic stem cells.
    • Clinical Importance: Myelosuppression leads to neutropenia, increasing the risk of bacterial and fungal infections.

---

Relevance

1. Diagnosis: Immunodeficiency is identified based on clinical history (recurrent infections, failure to thrive), laboratory tests (lymphocyte subsets, immunoglobulin levels, genetic testing), and functional immune assays.
2. Differential Diagnosis: Immunodeficiency should be differentiated from chronic inflammatory conditions and malignancies that can present with recurrent infections. 

Autoimmunity

 

Autoimmunity

 Definition

Autoimmunity refers to an immune response in which the body's immune system mistakenly targets its own cells, tissues, or organs, leading to self-reactivity (loss of tolerance to self-antigens). This can result in autoimmune diseases, which may be organ-specific (targeting a single organ) or systemic (affecting multiple systems).

---

Causes of Autoimmunity (All Dimensions)

1. Genetic Factors

• HLA (Human Leukocyte Antigen) Association – Certain HLA genes predispose individuals to autoimmunity (e.g., HLA-DR3/DR4 in Type 1 Diabetes).
• Gene Mutations & Polymorphisms – Variants in genes regulating immune tolerance (e.g., CTLA-4, PTPN22) can trigger self-reactivity.
• Familial Clustering – Autoimmune diseases often run in families due to shared genetic risk factors.

2. Environmental Triggers

• Infections – Molecular mimicry (microbial antigens resemble self-antigens, e.g., Streptococcus infection in Rheumatic fever).
• Toxins & Drugs – Exposure to chemicals (e.g., Procainamide-induced lupus, mercury exposure) can break self-tolerance.
• Dietary Factors – Gluten in genetically predisposed individuals (Celiac Disease).
• Radiation & UV Exposure – DNA damage leading to lupus flares in Systemic Lupus Erythematosus (SLE).

3. Immunological Factors

• Defective Central Tolerance – Failure in thymic deletion of autoreactive T-cells (e.g., Autoimmune Polyendocrine Syndrome Type 1 - AIRE gene mutation).
• Defective Peripheral Tolerance – Dysfunction in regulatory T-cells (Tregs), leading to uncontrolled immune activation.
• Bystander Activation – Non-specific activation of immune cells (e.g., viral infections leading to Multiple Sclerosis).
• Epitope Spreading – Immune response against an antigen expands to attack self-tissues (e.g., epitope spreading in Pemphigus vulgaris).

4. Hormonal Influence

• Female Predominance – Estrogen enhances immune response (SLE is more common in women).
• Pregnancy & Postpartum Changes – Immune shifts during pregnancy can either worsen or improve autoimmune conditions (e.g., RA improves in pregnancy but flares postpartum).

5. Psychological & Neurological Influence

• Chronic Stress – Elevation of cortisol can dysregulate immune responses, promoting inflammation in conditions like Multiple Sclerosis.
• Neuroimmune Interaction – Dysregulation of the gut-brain axis (e.g., Microbiome shifts in autoimmune diseases).

---

Mechanisms of Autoimmunity

1. Loss of Immune Tolerance

• Central Tolerance Failure (Thymus/Bone Marrow) – Ineffective deletion of self-reactive T/B cells.
• Peripheral Tolerance Failure – Regulatory T-cells (Tregs) fail to suppress autoimmunity.

2. Molecular Mimicry

• Example – Streptococcal M-protein resembles heart tissue, leading to Rheumatic Heart Disease.

3. Bystander Activation

• Example – Hepatitis C infection triggering immune-mediated vasculitis (Cryoglobulinemia).

4. Epitope Spreading

• Example – Autoimmune destruction spreads in Myasthenia Gravis, affecting multiple neuromuscular junction sites.

---

Examples of Autoimmune Diseases

Organ-Specific Autoimmune Diseases

• Type 1 Diabetes Mellitus – Autoimmune attack on pancreatic β-cells (Insulin-producing cells).
• Graves' Disease – Autoantibodies stimulating TSH receptors (thyroid hormone overproduction).
• Hashimoto’s Thyroiditis – Lymphocytic destruction of the thyroid gland.
• Addison’s Disease – Autoimmune destruction of the adrenal cortex.
• Pernicious Anemia – Autoimmune attack on parietal cells (intrinsic factor deficiency → B12 malabsorption).

Systemic Autoimmune Diseases

• Systemic Lupus Erythematosus (SLE) – Immune complexes deposit in multiple organs (skin, kidneys, joints).
• Rheumatoid Arthritis (RA) – Chronic inflammation of the synovium (joint lining).
• Sjogren’s Syndrome – Autoimmune destruction of salivary and lacrimal glands (dry eyes, dry mouth).
• Systemic Sclerosis (Scleroderma) – Fibrosis and autoimmunity affecting skin, lungs, kidneys.

Neurological Autoimmune Diseases

• Multiple Sclerosis (MS) – Demyelination of CNS neurons by autoreactive T-cells.
• Myasthenia Gravis – Autoantibodies blocking acetylcholine receptors at the neuromuscular junction.

Autoimmune Hematological Disorders

• Autoimmune Hemolytic Anemia – Destruction of RBCs by autoantibodies.
• Idiopathic Thrombocytopenic Purpura (ITP) – Autoantibodies against platelets.

Gastrointestinal Autoimmune Diseases

• Celiac Disease – Autoimmune response against gluten (HLA-DQ2/DQ8 association).
• Inflammatory Bowel Disease (IBD) – Crohn’s Disease, Ulcerative Colitis (chronic intestinal inflammation).

---

Diagnostic Markers in Autoimmune Diseases

• Antinuclear Antibody (ANA) – SLE, Scleroderma, Sjogren’s Syndrome.
• Rheumatoid Factor (RF), Anti-CCP – Rheumatoid Arthritis.
• Anti-dsDNA, Anti-Smith – SLE.
• Anti-TPO, Anti-TG – Hashimoto’s Thyroiditis.
• HLA Typing – Genetic predisposition in various diseases.

---

Treatment Approaches

1. Immunosuppressive Therapy

2. Symptomatic Management

3. Lifestyle & Complementary Approaches

• Dietary Modifications – Gluten-free diet in Celiac Disease.
• Gut Microbiome Modulation – Probiotics, fiber-rich diet for IBD.
• Stress Reduction – Yoga, meditation for chronic autoimmune conditions.

---

Conclusion

Autoimmunity results from a complex interplay of genetic, environmental, hormonal, and immunological factors. Understanding the diverse mechanisms helps in early diagnosis, personalized treatment, and improved management of autoimmune diseases.