Immunological Disorders

Immunological Disorders

Immunological disorders occur when the normal regulatory checkpoints or effector arms of the immune system fail. These disorders fall into three major categories: Autoimmunity (failure of self-tolerance), Hypersensitivity (tissue injury due to excessive or inappropriate immune responses), and Immunodeficiency (defects in the immune system that lead to increased susceptibility to infections).

1. Autoimmunity and Autoimmune Diseases

Autoimmunity is the presence of an immune response directed against self-antigens (autoantibodies, autoreactive T cells), which can cause structural or functional organ damage.

Mechanisms of Induction

• Release of Sequestered Antigens: Self-antigens sheltered in anatomically isolated sites (interior of the eye, spermatozoa in testes, myelin, heart muscle) never encounter developing lymphocytes during central tolerance. Trauma, infection, or surgery releases them into systemic circulation, provoking autoantibodies (e.g., sympathetic ophthalmia, post-infarction carditis, spontaneous infertility).
• Molecular Mimicry: Microbial epitopes share structural homology with self-peptides. Cross-reacting antibodies raised against Streptococcus pyogenes attack human cardiac myosin in rheumatic fever, or cross-react with neural tissues in post-rabies encephalitis.
• Inappropriate MHC Class II Expression: Aberrant upregulation of Class II MHC on non-APCs exposes self-epitopes to helper T cells (e.g., pancreatic beta cells in Type 1 Diabetes; thyroid acinar cells in Graves' disease).
• Polyclonal B-Cell Activation: Pathogens like Epstein-Barr virus (EBV) or Gram-negative bacterial lipopolysaccharides activate B cells non-specifically, generating antinuclear antibodies, rheumatoid factors, etc.
• Antigenic Alteration (Neoantigens): Chemical modification (drugs like penicillin or procainamide), physical injury (UV radiation), or enzymatic alterations render self-proteins immunogenic.
• Failure of Central/Peripheral Tolerance: Mutations in transcription factors like AIRE trigger widespread, fatal multiorgan autoimmunity due to failed clonal deletion or absence of functional regulatory T cells.

Autoimmune diseases are grouped into four clinical and pathological categories:

• Hemocytolytic Autoimmune Diseases: Autoantibodies target circulating blood elements directly.
• Autoimmune Hemolytic Anemia: Autoantibodies directed against red blood cell membrane proteins induce complement-mediated intravascular lysis or Fc-mediated opsonization and phagocytic clearance in the spleen.
• Idiopathic Thrombocytopenic Purpura: Autoantibodies bind platelet membrane glycoproteins, accelerating clearance and leading to bleeding symptoms such as nosebleeds, bleeding gums, hematuria, and impaired coagulation.
• Autoimmune Leukopenia: Antibodies target leukocytes, resulting in a marked drop in white blood cell counts.
• Localized (Organ-Specific) Autoimmune Diseases: Pathological injury remains confined to a single target organ.
• Hashimoto’s Thyroiditis (Lymphadenoid Goitre): Sensitised TH cells and autoantibodies target thyroid proteins (thyroglobulin and thyroid peroxidase). Dense lymphocytic and plasma cell infiltration results in visible thyroid enlargement (goitre) and hypothyroidism due to impaired iodine uptake.
• Graves’ Disease (Thyrotoxicosis): Autoantibodies act as agonists, binding directly to thyroid-stimulating hormone receptors (TSH-R). These long-acting thyroid-stimulating (LATS) antibodies continually overstimulate thyroxine and triiodothyronine synthesis.
• Myasthenia Gravis: Autoantibodies act as antagonists, binding acetylcholine receptors on skeletal muscle. This blocks normal neuromuscular transmission and recruits complement to destroy the cells, clinically causing drooping eyelids, facial muscle weakness (snarling appearance), and progressive motor fatigue.
• Goodpasture’s Syndrome: Autoantibodies attack collagen in the glomerular basement membrane and pulmonary alveolar basement membranes and result in severe glomerulonephritis and pulmonary haemorrhage.
• Pernicious Anaemia: Autoantibodies against gastric parietal cells or intrinsic factor block intrinsic factor-mediated absorption of vitamin B12, this will influence normal erythropoiesis, leading to anaemia.
• Insulin-Dependent Diabetes Mellitus: Cytotoxic T lymphocytes, autoantibodies, and macrophage-derived lytic enzymes selectively destroy insulin-producing beta cells within pancreatic islets of Langerhans, causing insulin deficiency.
• Addison's Disease: Lymphocytic infiltration of the adrenal cortex and circulating autoantibodies against the zona glomerulosa result in primary hypocortisolism, muscle weakness, weight loss, and hyperpigmentation.
• Autoimmune skin Conditions: Includes Pemphigus vulgaris (autoantibodies against intercellular cement substances producing blisters), Bullous pemphigoid (antibodies targeting the dermal-epidermal basement membrane junction), and Dermatitis herpetiformis (papulovesicular eruptions).
• Ocular Conditions: Includes Sympathetic ophthalmia (ocular inflammation following perforating injury releasing sequestered uveal proteins) and Phacoanaphylaxis (intraocular inflammation after cataract surgery against sequestered lens antigens).
• Autoimmune orchitis – It develops following mumps infection when acute inflammation disrupts the blood-testis barrier, exposing sequestered sperm neoantigens to the immune system. This breach triggers the production of anti-sperm antibodies and lymphocytic infiltration, leading to sperm agglutination, germ cell atrophy, and potential sterility.
• Systemic Autoimmune Diseases: A generalised failure in immune regulation drives widespread tissue injury mediated by immune complexes and autoantibodies
• Systemic Lupus Erythematosus (SLE): Typically presents in women aged 20–40 with fever, polyarthritis, butterfly (malar) facial rash, pleurisy, and nephritis. Pathogenesis involves antinuclear antibodies (ANAs against dsDNA, histones, ribonucleoproteins), which generate circulating immune complexes that deposit in blood vessels and kidneys (Type III hypersensitivity), while anti-RBC and anti-platelet antibodies drive cytopenias (Type II hypersensitivity). Histopathology reveals LE cells—phagocytes containing ingested, denatured nuclear material (LE bodies).
• Rheumatoid Arthritis (RA): Autoreactive B cells produce Rheumatoid Factor (RF), typically an IgM autoantibody that binds the Fc region of self-IgG. IgM-IgG complexes deposit into synovial membranes, activating complement and recruiting neutrophils to drive joint destruction.
• Scleroderma (Systemic Sclerosis): Collagen deposition leads to skin hardening and visceral fibrosis.  Diffuse scleroderma (rapid visceral involvement of lungs, kidneys, and heart) and Limited scleroderma / CREST syndrome (Calcinosis, Raynaud's phenomenon, Esophageal dysmotility, Sclerodactyly, Telangiectasia).
• Multiple Sclerosis (MS): Autoreactive TH cells and cytotoxic T cells cross the compromised blood-brain barrier and infiltrate CNS white matter, stripping myelin sheaths and causing sensory and motor deficits.
• Sjogren’s Syndrome: Autoimmune destruction of exocrine moisture-producing glands leads to xerostomia (dry mouth) and conjunctivitis sicca (dry eyes).
• Ankylosing Spondylitis and Polyarteritis Nodosa: Chronic inflammation of joints, or necrotizing vasculitis of medium-sized arteries resulting in visceral thrombosis and hemorrhages.
• Transitory Autoimmune Diseases: Transient forms of anemia, thrombocytopenia, or nephritis triggered after specific microbial infections or drug therapies that resolve spontaneously when the drug or pathogen is eliminated.

 

 

 

2. Hypersensitivity Reactions (Gell-Coombs Classification)

Hypersensitivity reactions are exaggerated, inappropriate immune responses to exogenous or endogenous antigens that produce tissue destruction. They require prior exposure (sensitisation) before subsequent exposure triggers clinical disease.

Type	Immune Mediator	Effector Mechanism	Classic Examples
Type I (Immediate / Atopic)	IgE antibodies on mast cells and basophils	Cross-linking triggers degranulation: primary mediators (histamine, serotonin) and secondary mediators	Systemic anaphylaxis, allergic asthma, hay fever (allergic rhinitis), food allergies (peanuts, shellfish), urticaria.
Type II (Cytotoxic / Antibody-Mediated)	IgG or IgM directed against cell-surface or tissue antigens	Complement-mediated lysis, opsonization/phagocytosis, or ADCC by NK cells, receptor stimulation/blockade	Hemolytic disease of the newborn (erythroblastosis fetalis), ABO transfusion reactions, Goodpasture's syndrome, Graves' disease, Myasthenia gravis, autoimmune hemolytic anemia.
Type III (Immune Complex-Mediated)	Soluble antigen- IgG/IgM complexes	Complex deposition in vascular basement membranes - complement activation - neutrophil recruitment - lysosomal enzyme release	Arthus reaction (localized), Serum sickness (systemic), Systemic lupus erythematosus (SLE), Rheumatoid arthritis, Post-streptococcal glomerulonephritis, Farmer's lung.
Type IV (Delayed-Type / Cell-Mediated)	Sensitized TH cells and cytotoxic TC cells	Release of cytokines  - recruitment and activation of macrophages - epithelioid/giant cell granuloma formation or direct cytolysis	Tuberculin skin test (Mantoux), Contact dermatitis (nickel, poison ivy urushiol), chronic graft rejection, Multiple sclerosis, granulomatous response in M. tuberculosis.

The four types of hypersensitivity according to the Gell–Coombs classification are:

• Type I (IgE-Mediated / Anaphylactic) Hypersensitivity:

Exposure to an allergen cross-links membrane-bound IgE, triggering cell degranulation and the release of vasoactive mediators, including primary mediators (histamine, serotonin) and secondary lipid mediators (leukotrienes/SRS-A, prostaglandins, and platelet-activating factor).

Clinical Manifestations are Systemic anaphylaxis, allergic asthma, allergic rhinitis (hay fever), hives (urticaria), and food allergies.

• Type II (IgG/IgM-Mediated Cytotoxic) Hypersensitivity:

IgG or IgM antibodies are directed against self-cell surfaces or tissue antigens. Antibody binding mediates target cell destruction through complement-mediated lysis (membrane attack complex formation), opsonization followed by phagocytosis, or antibody-dependent cell-mediated cytotoxicity (ADCC).

Clinical Manifestations are ABO blood transfusion reactions, erythroblastosis fetalis (hemolytic disease of the newborn), drug-induced hemolytic anemia, and autoimmune hemolytic anemia.

• Type III (Immune Complex-Mediated) Hypersensitivity:

Antibody (IgM or IgG) complexes with soluble antigens and forms circulating immune complexes.  These precipitate and deposit into vascular basement membranes (in blood vessels, kidney glomeruli, or joints). These deposits activate complement components (C3a, C5a), which attract neutrophils that release lytic enzymes during frustrated phagocytosis, causing localized tissue necrosis and inflammation.

Clinical Manifestations are Arthus reaction (localized), serum sickness (generalized), post-streptococcal glomerulonephritis, systemic lupus erythematosus (SLE), and rheumatoid arthritis.

• Type IV (Cell-Mediated / Delayed-Type) Hypersensitivity:

Immune mediators are sensitized TH cells and cytotoxic T lymphocytes (TC). Upon secondary antigen challenge, sensitized TH1 cells secrete cytokines/lymphokines that recruit and activate blood monocytes into macrophages at the site within 48 to 72 hours. Macrophage accumulation and the release of their lytic enzymes mediate tissue destruction and granuloma formation.

Clinical Manifestations are Allergic contact dermatitis (e.g., to nickel, cosmetics, or poison ivy/oak pentadecacatechol), tubercular granulomatous lesions, and graft rejection.

 

3. Immunodeficiency Diseases

Immunodeficiencies occur when components of the innate or adaptive immune system are absent, impaired, or destroyed, rendering the patient susceptible to opportunistic and recurrent infections.

Primary or Congenital Immunodeficiencies

Genetically determined defects manifesting in infancy or early childhood:

• B-Cell (Humoral) Deficiencies:
• X-Linked Agammaglobulinemia (Bruton’s): Mutation in Bruton tyrosine kinase (BTK) prevents B-cell maturation, resulting in absence of mature B cells and a lack of all immunoglobulin classes. Manifests as recurrent pyogenic bacterial infections once the levels of maternal antibodies wane.
• Selective IgA Deficiency: The most common primary immunodeficiency. Often asymptomatic, but can present with recurrent sinopulmonary and gastrointestinal mucosal infections.
• T-Cell (Cell-Mediated) Deficiencies:
• DiGeorge Syndrome (Thymic Hypoplasia): Congenital 22q11.2 microdeletion (chromosomal deletion on the long arm of chromosome 22). Results in thymic aplasia, profound T-cell deficiency, hypocalcemia (parathyroid aplasia), and cardiac defects. The thymus gland is missing or underdeveloped, so the body cannot produce enough mature T cells, leaving the child vulnerable to frequent viral and fungal infections.
• Combined Deficiencies:
• Severe Combined Immunodeficiency (SCID): This is a rare and fatal genetic disorder where the individual does not have a functional immune system.  It got the nickname "bubble boy disease" because a famous patient named David Vetter lived inside a special plastic, germ-free isolation bubble for 12 years in the 1970s and 1980s.  This is a life-threatening primary immunodeficiency caused by mutations such as common gamma chain deficiency (X-linked) or adenosine deaminase (ADA) deficiency. Both T and B cells fail to develop or function and, infants suffer severe opportunistic infections and failure to thrive, resulting in early mortality unless cured via hematopoietic stem cell transplantation (HSCT) or targeted gene therapy.
• Phagocytic and Complement Deficiencies:
• Chronic Granulomatous Disease (CGD): Defect in the NADPH oxidase enzyme complex impairs phagocytes from generating reactive oxygen species, leading to severe recurrent infections by catalase-positive organisms (e.g., Staphylococcus aureus, Aspergillus).
• Terminal Complement Deficiencies: Inability to assemble the Membrane Attack Complex by the complement cascade, predisposing patients to invasive Neisseria meningitidis and Neisseria gonorrhoeae infections.

Secondary or Acquired Immunodeficiencies

Induced by environmental factors, drugs, systemic illnesses, or pathogens:

• Acquired Immunodeficiency Syndrome (AIDS): Caused by Human Immunodeficiency Virus (HIV). The viral gp120 binds to CD4 on helper T cells, macrophages, and dendritic cells. The ensuing depletion of CD4 T cells compromises both cell-mediated immunity and humoral activation, causing life-threatening opportunistic infections (e.g., Pneumocystis, Cytomegalovirus) and malignancies (Kaposi's sarcoma).
• Iatrogenic Immunodeficiency: Induced by therapeutic interventions, such as high-dose corticosteroids, cytotoxic chemotherapy (cyclophosphamide, methotrexate), radiation therapy, or targeted immunosuppressive agents used in transplantation and autoimmune control.
• Malnutrition and Metabolic States: Severe protein-energy malnutrition causes lymphoid tissue atrophy; advanced chronic kidney disease  and diabetes mellitus impair leukocyte chemotaxis and phagocytosis.