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.

 

Immunological Tolerance

 Immunological Tolerance

Immune tolerance or immunological tolerance is the process by which the immune system does not attack an antigen. It can be either natural or self-tolerance, in which the body does not mount an immune response to self-antigens, or induced tolerance, in which tolerance to external antigens can be created by manipulating the immune system through the administration of antigen according to certain regimens.

Self-tolerance is the immune system's inability to mount an attack against autologous (host) antigens.  This serves as the critical boundary between self and non-self. When these regulatory checks fail, the immune system targets the body's own tissues, directly causing autoimmune disease.

Induced tolerance is created therapeutically or experimentally to silence harmful immunological reactions against specific antigens while leaving the rest of the immune system fully functional.

Antigens that induce tolerance are called tolerogens. Whether an encounter leads to immunity or tolerance depends on the antigen's structure, concentration, route of entry, co-stimulatory context, and the maturation stage of the encountering lymphocyte.   Immunological tolerance is not failure to recognise an antigen.  It is an active response to a particular epitope and is specific, as an immune response.  Both B cells and T cells can be made tolerant, but T cell tolerance is more important than B cell tolerance because B cells cannot make antibodies to most antigens without the help of T cells.

Immunological Tolerance occurs in three forms: central tolerance, Peripheral tolerance and acquired tolerance.

1. Central Tolerance

Central tolerance occurs during early lymphocyte development within primary lymphoid organs, the thymus for T lymphocytes and the bone marrow for B lymphocytes.

T-Cell Central Tolerance (in Thymus)

• Positive Selection (Cortex) - Immature double-positive (CD4+ CD8+) thymocytes interact with self MHC complexes on cortical thymic epithelial cells. Cells with weak-to-moderate affinity receive survival signals and commit to either single-positive CD4+ or CD8+ lineages. Cells with no affinity undergo death by neglect.
• Negative Selection (Medulla) - Single-positive thymocytes interact with medullary thymic epithelial cells and dendritic cells. High-affinity binding to self-antigen–MHC triggers apoptosis (clonal deletion).  antigen-presenting cells in the medulla of the thymus express a gene, AIRE, that encodes a transcription factor that turns on the expression of hundreds of tissue-specific genes encoding various proteins such as insulin, thyroglobulin, and retinal proteins.
• Generation of tTregs: tTreg (Thymus-Derived Regulatory T Cell), is a specialized subset of regulatory T lymphocytes that develops and matures within the thymus to actively enforce immunological self-tolerance.  During negative selection, while clones with excessively high affinity for self-peptide–MHC complexes are deleted by apoptosis, thymocytes that recognize self-antigens with an intermediate-to-high affinity receive survival and differentiation signals to develop into the regulatory T-cell lineage. Their self-reactivity ensures that they are physically present at the site of self-antigens, where their inhibitory machinery neutralizes any conventional autoreactive T cells that escaped clonal deletion.

B-Cell Central Tolerance (in Bone Marrow)

Immature B cells expressing surface IgM encounter multivalent self-antigens in the bone marrow stroma. One of four fates follows:

• Receptor Editing: Strong cross-linking of surface IgM induces re arrangement of autoreactive light chain so that a non-autoreactive antibody results.
• Clonal Deletion: If receptor editing fails to eliminate high-affinity self-reactivity, the cell undergoes apoptotic death.
• Anergy: Exposure to soluble, self-antigens downregulates surface IgM and uncouples signal transduction, rendering the cell functionally inactive.
• Ignorance: Low-affinity self-antigen binding cells are ignored, the cells exit to the periphery without deletion because the antigen is either undetectable or inaccessible.

2. Peripheral Tolerance

Since some self-antigens are absent in primary lymphoid organs, and lower-affinity self-reactive clones escape, central tolerance is incomplete.  So secondary lymphoid tissues and peripheral sites enforce peripheral tolerance. 

B cells with a potential for attacking self can be kept under control by the absence of the T-helper cells.  T-cell tolerance is probably the most important mechanism for maintaining B-cell tolerance.

Negative Selection in the Peripheral Immune System - AIRE is also active in some APC in the organs of the peripheral immune system (lymph nodes and spleen). So any potentially autoreactive T cells that failed to be eliminated in the thymus are deleted here.

Lack of Costimulation is a primary mechanism of peripheral tolerance that prevents mature, self-reactive T cells from attacking healthy tissues when they encounter self-antigens outside the thymus. T-cell activation strictly requires two signals: Signal 1 (TCR recognition of peptide-MHC) and Signal 2 (co-stimulation via CD28 binding B7 on mature APCs). Lack of co-stimulation leads to prolonged, antigen-specific hypo responsiveness.

Failure to Encounter Self Antigens - Some tissues are hidden behind anatomical barriers that keep T cells from reaching them. Examples of such "privileged sites" are Interior of the eye, testes and brain.  Mechanical damage can breach the barrier and an autoimmune reaction follow.

Receipt of Death Signals - Some cells of the body express FasL.  Activated T cells always express Fas.  When they encounter these cells, binding of Fas to FasL triggers T cell death by apoptosis.

Control by Regulatory T Cells - Regulatory T cells, suppresses the activity of other T cells.

3. Induced or acquired tolerance

This is the deliberate manipulation of the immune system to establish antigen-specific unresponsiveness toward external or non-self antigens.

• Acquired tolerance against allergens - In allergic individuals, the immune system fails to maintain natural tolerance toward harmless environmental antigens (allergens).  There will be hypersensitivity response towards such allergens. Inducing acquired tolerance against such allergens help such individuals.  Inducing Tolerance can be done by allergen immunotherapy or desensitization.  Clinically, tolerance is induced by administering tiny, gradually escalating doses of the allergen over an extended period.
• Transplant Tolerance: Inducing tolerance to allografts allows the transplant to survive long-term without continuous immunosuppressive drugs. This graft tolerance is typically established when donor cells fail to deliver costimulatory second signals to host T cells, and it is maintained by the persistence and survival of donor cells within the recipient.
• Tolerance of the Fetus: The human fetus functions immunologically as an allograft expressing paternal antigens, yet the maternal immune system actively refrains from rejecting it throughout gestation. This is due to anatomical sequestration, absence of costimulatory second signals, enforcement by regulatory t cells, etc.

Factors determining the induction, extent, and duration of tolerance

1. Competence of the immune system - tolerance develops much more readily in animals with immature immune systems (neonates) or in adults whose immune competence has been compromised by irradiation, immunosuppressive drugs, or thoracic duct drainage.

2. Molecular characteristics of the antigen - polymeric or aggregated molecules induce immunity, whereas monomeric or deaggregated forms induce tolerance. Polymeric salmonella adelaide flagellin (104 kDa) is highly immunogenic, but its monomeric form (4 kDa) is tolerogenic at high doses, and a smaller 1.8 kDa fragment induces tolerance even at low doses.  Also, chemical modifications can convert an immunogen into a tolerogen.

3. Dose of the antigen – high concentration of antigen induces tolerance, subimmunogenic amounts administered over prolonged periods induces tolerance.  In general, intermediate doses stimulate an active immune response, whereas both low and high extremes drive tolerance. 

4. Route of administration - intravenous and intraperitoneal dose induce tolerance, mucosal exposure via feeding regularly induce tolerance, subcutaneous route induced active immunity.

5. Persistence of the antigen - sustained tolerance requires the physical persistence and accessibility of the tolerogen to continuously neutralize newly emerging naive T and B cells.

6. Termination of tolerance - the tolerant state is not permanent and gradually wanes over time.

7. Genetic susceptibility - tolerance induction is genetically controlled.  Balb/c mice exhibit genetic resistance to tolerance induction

8. Costimulatory signals -  the lack of signal 2 (CD28 binding to b7 on APCs) determines whether a T cell undergoes anergy/apoptosis or activation.

 

 

 

Cell mediated immune response- self MHC restriction, T cell activation, co-stimulatory signals, killing mechanism by CTL and NK cells

Cell mediated immune response- self MHC restriction, T cell activation, co-stimulatory signals, killing mechanism by CTL and NK cells

Cell-Mediated Immunity  

Cell-mediated immunity (CMI) is the branch of the adaptive immune system directed against intracellular pathogens (viruses, intracellular bacteria, parasites), altered-self cells (tumour cells), and graft tissue.

Cell-mediated immunity relies on both antigen-specific lymphocytes (CD4 TH cells and CD8 Cytotoxic T Lymphocytes) and non-specific effector cells (NK cells, macrophages, neutrophils, and eosinophils).  Local cytokines secreted primarily by T cells, NK cells, and macrophages coordinate and sustain the activity of all these cells.  Cell-mediated and humoral immunity actively cooperate: non-specific immune cells use antibodies to target cells for killing (ADCC), and complement activation (in response to antigen-antibody complexes) recruits leukocytes to the site of infection.

Cell-mediated immune responses fall into two broad functional categories based on their effector cells:

• Direct Cytotoxic Effectors (Target Lysis): Cells that directly eliminate foreign, malignant, virus-infected, or chemically modified cells through cytolytic reactions.  These cells directly destroy virally infected cells, tumor cells, and foreign tissue grafts by triggering targeted apoptosis via the perforin/granzyme or Fas/FasL pathways.
• Antigen-Specific:  CD8+ Cytotoxic T Lymphocytes (CTLs).
• Antigen-Nonspecific: Natural Killer (NK) cells and activated macrophages.
• Delayed-Type Hypersensitivity (TH Effectors): A specialized subpopulation of effector CD4+ T cells that mediate inflammatory responses and macrophage activation rather than direct cell lysis.  They release potent inflammatory cytokines (IFN-γ and TNF-α) to activate tissue macrophages, recruit granulocytes, and wall off persistent intracellular microbes.

Self-MHC Restriction of T Cells

T lymphocytes do not recognize free, soluble antigen. Their αβ TCRs recognise antigen only as degraded peptide fragments presented by self-MHC molecules.  This is termed self-MHC restriction.

Feature	CD4+ Helper T Cell (TH​)	CD8+ Cytotoxic T Cell (TC​ / CTL)
Co-receptor	CD4	CD8
MHC Restriction	MHC Class II	MHC Class I
Antigen Source	Exogenous (extracellular pathogens)	Endogenous (intracellular/viral / tumour)
Presented by	Professional APCs only (Dendritic cells, Macrophages, B cells)	All nucleated cells (any infected target cell)
Primary Function	Secretes cytokines to help B cells and activate macrophages	Directly kills infected or abnormal target cells via apoptosis

 

 Generation of the MHC-Restricted Repertoire in Thymus

Self-MHC restriction is acquired during T-cell maturation in the thymus through a two-step selection process to produce functional, non-autoreactive T cells:

• Positive Selection (Cortex): Immature double-positive (CD4+ CD8+) thymocytes interact with cortical epithelial cells displaying self-MHC Class I and II molecules. Cells with T-cell receptors (TCRs) that recognise self-MHC with low-to-moderate affinity receive essential survival signals, while non-binding cells die by neglect; this step establishes self-MHC restriction.  Thymocytes lose their double-positive (CD4+ CD8+) nature during and following positive selection in the thymic cortex, as they transition into single-positive (CD4+ or CD8+) cells.
• Negative Selection (Cortex and Medulla): Surviving thymocytes are screened by dendritic cells and macrophages presenting self-peptides on self-MHC. Thymocytes whose TCRs bind self-antigens with high affinity are eliminated via apoptosis (clonal deletion); this step establishes central self-tolerance.

After completing positive and negative selection in the thymus, surviving single-positive (CD4+ or CD8+) T cells exit into the peripheral circulation as naive T cells. Upon encountering their specific antigen, they proliferate and differentiate into effector T cells.

How a Naive T Cell Becomes Effector and Memory Cells

1.    Activation - A naive T cell in a lymph node encounters a dendritic cell displaying specific antigen alongside co-stimulatory signals. This triggers rapid cell division (clonal expansion).

2.    Effector Differentiation - Most of the dividing cells become effector T cells (TC or CTLs). They leave the lymph nodes, travel to the infected tissue, and actively clear the pathogen by secreting cytokines or killing infected cells. Once the infection is eliminated, over 90% of these effector cells die off by apoptosis.

3.   Memory Cell Formation - A small subset (5-10%) of the cells survives and differentiates into memory T cells. Supported by survival cytokines (IL-7 and IL-15), they live for years or decades to provide immediate, highly potent protection upon reexposure.

Cytotoxic T Cells

Cytotoxic T lymphocytes, or CTLs, are generated by immune activation of T cytotoxic (TC) cells. These effector cells have lytic capability and are critical in the recognition and elimination of altered self-cells.  Since all nucleated cells in the body express class I MHC molecules, CTLs can recognize and eliminate almost any altered body cell.

The CTL-mediated immune response can be divided into two phases, reflecting different aspects of the response. The first phase activates and differentiates naive TC cells into functional effector CTLs. In the second phase, effector CTLs recognise antigen–class I MHC complexes on specific target cells, which leads them to destroy the target cells.

Naive TC cells are incapable of killing target cells and are therefore referred to as CTL precursors (CTL-Ps).

Naive T-cell activation occurs through an immunological synapse formed with an antigen-presenting cell (APC), where multiple receptor–ligand pairs cluster together.  Generation of CTLs from CTL-Ps requires at least three sequential signals  

1. An antigen-specific signal 1 transmitted by the TCR complex upon recognition of a peptide–class I MHC molecule complex

2. A co-stimulatory signal transmitted by the CD28-B7 interaction of the CTL-P and the antigen-presenting cell

3. A signal induced by the interaction of IL-2 with the high-affinity IL-2 receptor, resulting in proliferation and differentiation of the antigen-activated CTL-P into effector CTLs

Generation of effector CTLs (Kuby Immunology) 

While naive cytotoxic T-lymphocyte precursors (CTL-Ps) rely on TH cells for IL-2 and enhanced CD28–B7 co-stimulation to proliferate, memory CTL-Ps can auto secrete sufficient IL-2 and differentiate into effector CTLs without needing TH help or CD28–B7 co-stimulation.

Cytotoxic T Lymphocytes (CD8+ CTLs) eliminate virus-infected, tumor, and foreign cells by inducing programmed cell death (apoptosis) via two primary pathways

(a)  The Fas pathway. Interaction of the membrane-bound Fas ligand on CTLs with the Fas receptor on the surface of target cells.  Ligation of trimeric Fas units by CTL-borne Fas ligand leads to the association of the death domains of Fas with FADD, which in turn results in a series of reactions leading to apoptosis of the target cell.

(b)  The perforin/granzyme pathway. Directional delivery of cytotoxic proteins (perforin and granzymes) that are released from CTLs and enter target cells.  Granule exocytosis releases granzymes and perforin from the CTL into the space between the CTL and the target cell. Granzyme B enters the target cell in two ways: via perforin-generated pores, or by binding to mannose 6-phosphate receptors that are subsequently endocytosed. Granzyme B is then released into the cytoplasm in a perforin-dependent process. Cleavage of procaspase 8 by granzyme B activates a caspase cascade that results in the apoptotic death of the cell, and interaction of granzyme B with other targets can invoke mitochondrially mediated death pathways. While Granzyme B rapidly kills targets by activating the caspase cascade, many viruses and tumors have evolved caspase inhibitors to block this process. To counteract this, CTLs also load their granules with Granzyme A, providing a guaranteed, caspase-independent pathway that destroys the target cell's mitochondria and DNA if the primary pathway is blocked.

Either of these events results in the activation of a signalling pathway that culminates in the death of the target cell by apoptosis

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Natural Killer Cell (NK Cell) Recognition and Killing

NK cells are large granular lymphocytes of the innate immune system that provide early defence against viral infection and malignancy without prior sensitization, clonal expansion, or MHC presentation.  NK cells are involved in the early response to infection with certain viruses and intracellular bacteria. NK activity is stimulated by IFN-α, IFN-β, and IL-12.  Natural Killer (NK) cells provide the crucial first line of defense against viral infection until naïve CTL precursors fully activate, proliferate, and differentiate into functional effector CTLs, which takes around 7 days.

Natural Killer (NK) cells eliminate virus-infected and tumor targets using the same two apoptotic pathways as cytotoxic T lymphocytes (CTLs): perforin/granzyme degranulation and FasL-mediated death induction.  NK cells bear FasL on their surface and readily induce death in Fas-bearing target cells. The cytoplasm of NK cells contains numerous granules containing perforin and granzymes. Unlike CTLs, which need to be activated before granules appear, NK cells are constitutively cytotoxic, always having large granules in their cytoplasm.

NK cells differ from CTLs in several significant ways. First, NK cells do not express antigen specific T-cell receptors or CD3. Recognition of target cells by NK cells is not MHC restricted.  NK-cell response generates no immunologic memory.

Unlike T cells, Natural Killer (NK) cells lack antigen-specific receptors.  NK cell activation is governed by the balance-of-signals model. NK activation is set by the dynamic balance between inhibitory and activating surface receptor signals. 

Three pathways to NK cell activation

·  ‘Missing-Self’ Recognition: Healthy cells continuously express self-MHC Class I, which engages NK inhibitory receptors (like KIRs) to suppress killing. When virus-infected or malignant cells downregulate MHC Class I to hide from cytotoxic T cells, this inhibitory "brake" is removed, and NK cells recognise such cells.

·  ‘Induced-Self’ (Stress-Induced) Recognition: Malignant, DNA-damaged, or infected cells upregulate stress-induced surface ligands (e.g., MICA/MICB). These bind to NK activating receptors (e.g., NKG2D), generating a strong activating signal for NK cell activation.

· Antibody-Dependent Cellular Cytotoxicity (ADCC): When host IgG antibodies bind foreign surface antigens on infected or tumor cells, the NK cell's CD16 receptor binds the exposed antibody Fc tails. Cross-linking multiple CD16 molecules provides a potent activating signal for NK cell activation.

ADCC is an immune mechanism where nonspecific effector cells with cytotoxic potential recognize and destroy target cells that are specifically coated with antibodies.   Cells that can mediate ADCC are NK cells, macrophages, monocytes, neutrophils, and eosinophils.

Mechanism of Action:

1. Antibody Binding: Antigen-specific antibodies  bind to surface antigens on infected, foreign, or malignant target cells via their Fab variable regions.

2. Fc Receptor Engagement: Cytotoxic effector cells express specialized membrane receptors, which bind to the exposed Fc tails of the target-bound antibodies.

3. Target Lysis: Crosslinking of Fc receptors activates the effector cell, triggering the polarized release of lytic factors (such as perforin/granzymes, lytic enzymes, or reactive oxygen intermediates) that lyse the target cell.

Antibody-dependent cell-mediated cytotoxicity (ADCC) (Kuby Immunology)

Comparative Summary: CTL vs NK Cell

Feature	Cytotoxic T Lymphocyte (CTL)	Natural Killer (NK) Cell
Immune System	Adaptive immunity	Innate immunity
Target Recognition	Needs specific viral antigen on MHC-I	Kills cells that lack MHC-I ("missing-self")
Response Speed	Delayed (needs ~7 days to activate & multiply)	Immediate (ready to kill within hours)
Granules	Produced after activation	Pre-formed (always present in cytoplasm)
ADCC Capability	No	Yes (binds antibody-coated cells via CD16)
Memory	Forms long-lasting memory cells	Little to no classical memory

 

 

Reference: Kuby Immunology