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 (excessive or inappropriate collateral tissue injury to antigens), and Immunodeficiency (defects in immune components leading 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.

• Witebsky’s Postulates: Criteria required to classify a disease as autoimmune:
1. Direct evidence: Transfer of pathogenic antibodies or pathogenic T cells reproduces the disease.
2. Indirect evidence: Reproduction of the disease in experimental animal models.
3. Circumstantial evidence: Clinical clues (female bias, family history, elevated serum immunoglobulins, therapeutic response to immunosuppressive therapy).
• General Hallmarks: High incidence among females, chronicity, genetic predisposition, elevated serum immunoglobulins, and autoantibody/lymphocytic infiltration at tissue lesion sites.

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 -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, and cold agglutinins.
• 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 Checkpoints: 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 epistaxis (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 or endocrine gland:
• Hashimoto’s Thyroiditis (Lymphadenoid Goitre): Sensitized  cells and autoantibodies target thyroid proteins, notably thyroglobulin and thyroid peroxidase. Dense lymphocytic and plasma cell infiltration forms ectopic germinal centers, resulting in visible thyroid enlargement (goiter) and secondary hypothyroidism due to blocked iodine uptake.
• Graves’ Disease (Thyrotoxicosis): Autoantibodies act as agonists, binding directly to thyroid-stimulating hormone receptors (TSH-R). Termed Long-Acting Thyroid Stimulating (LATS) antibodies, they bypass physiological feedback loops, continually overstimulating thyroxine () and triiodothyronine () synthesis.
• Myasthenia Gravis: Autoantibodies act as antagonists, binding nicotinic acetylcholine receptors (AChR) on skeletal muscle motor endplates. This blocks normal neuromuscular transmission and recruits complement to destroy the motor endplate, clinically causing ptosis (drooping eyelids), facial muscle weakness ("snarling" appearance), and progressive motor fatigue.
• Goodpasture’s Syndrome: Autoantibodies attack collagen in the glomerular basement membrane (GBM) and pulmonary alveolar basement membranes. Subsequent complement activation drives severe glomerulonephritis and pulmonary hemorrhage.
• Pernicious Anemia: Autoantibodies against gastric parietal cells or intrinsic factor block intrinsic factor-mediated absorption of vitamin B12 in the terminal ileum, halting normal erythropoiesis.
• Insulin-Dependent Diabetes Mellitus (IDDM / Type 1): Cytotoxic T lymphocytes, autoantibodies, and macrophage-derived lytic enzymes selectively destroy insulin-producing beta cells within pancreatic islets of Langerhans, causing absolute 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 Cutaneous 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 and Reproductive Conditions: Includes Sympathetic ophthalmia (ocular inflammation following perforating injury releasing sequestered uveal proteins), Phacoanaphylaxis (intraocular inflammation after cataract surgery against sequestered lens antigens), and Autoimmune orchitis (post-mumps orchitis where sperm-barrier breach provokes autoantibodies and sterility).
• Systemic Autoimmune Diseases: A generalized 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  autoantibody that binds the Fc region of self-. Formed  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. Divided into 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  and cytotoxic T cells traverse the blood-brain barrier and infiltrate CNS white matter, stripping myelin sheaths and causing sensory and motor deficits.
• Sjögren’s Syndrome: Autoimmune destruction of exocrine moisture-producing glands leads to xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes).
• Ankylosing Spondylitis & Polyarteritis Nodosa: Chronic inflammation of sacroiliac and vertebral 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 pharmaceutical therapies that resolve spontaneously when the offending 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 (sensitization) before subsequent exposure triggers clinical disease.

Type	Immune Mediator	Effector Mechanism	Classic Examples
Type I (Immediate / Atopic)	antibodies bound to  on mast cells & 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)	or  directed against cell-surface or tissue antigens	Complement-mediated lysis (MAC formation), 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-/ 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:
• Immune Mediator:  antibodies bound to Fc receptors on tissue mast cells and circulating basophils.
• Mechanism: Exposure to an allergen cross-links membrane-bound , 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: Systemic anaphylaxis, allergic asthma, allergic rhinitis (hay fever), hives (urticaria), and food allergies.
• Type II (IgG/IgM-Mediated Cytotoxic) Hypersensitivity:
• Immune Mediator:  or  antibodies directed against self-cell surfaces or tissue antigens.
• Mechanism: 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: 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:
• Immune Mediator: Soluble antigen–antibody ( or ) complexes.
• Mechanism: Circulating immune complexes precipitate and deposit into vascular basement membranes (in blood vessels, kidney glomeruli, or joints). These deposits activate complement components (), which attract neutrophils that release lytic enzymes during frustrated phagocytosis, causing localized tissue necrosis and inflammation.
• Clinical Manifestations: Arthus reaction (localized), serum sickness (generalized), post-streptococcal glomerulonephritis, systemic lupus erythematosus (SLE), and rheumatoid arthritis.
• Type IV (Cell-Mediated / Delayed-Type) Hypersensitivity:
• Immune Mediator: Sensitized  cells and cytotoxic  lymphocytes ().
• Mechanism: Upon secondary antigen challenge, sensitized  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: Allergic contact dermatitis (e.g., to nickel, cosmetics, or poison ivy/oak pentadecacatechol), tubercular granulomatous lesions, and graft rejection.

3. Immunodeficiency Diseases

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

Primary (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 beyond the pre-B stage; results in absent mature B cells and lack of all immunoglobulin classes. Manifests as recurrent pyogenic bacterial infections (e.g., Streptococcus pneumoniae, Haemophilus influenzae) after 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 deletion causing defective embryonic development of the 3rd and 4th pharyngeal pouches. Results in thymic aplasia, profound T-cell deficiency, hypocalcemia (parathyroid aplasia), and cardiac defects. Patients are susceptible to intracellular fungi, viruses, and protozoa.
• Combined Deficiencies:
• Severe Combined Immunodeficiency (SCID): 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. Fatal in infancy unless corrected by hematopoietic stem cell transplantation.
• 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 and granulomas from catalase-positive organisms (e.g., Staphylococcus aureus, Aspergillus).
• Terminal Complement Deficiencies (): Inability to assemble the Membrane Attack Complex (MAC), predisposing patients to invasive Neisseria meningitidis and Neisseria gonorrhoeae infections.

Secondary (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 surface  on helper T cells, macrophages, and dendritic cells. The ensuing depletion of  T cells compromises both cell-mediated immunity and humoral activation, causing life-threatening opportunistic infections (e.g., Pneumocystis jirovecii, 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 (uremia) and diabetes mellitus impair leukocyte chemotaxis and phagocytosis.