Hypersensitivity, Autoimmunity & Transplantation
Immunopathology: When Immune Defense Becomes Disease
1. Hypersensitivity Reactions (Gell and Coombs Classification)
Hypersensitivity is defined as an exaggerated, inappropriate immune response to an antigen (allergen or environmental molecule) upon secondary or subsequent contact. It results in host tissue damage, inflammation, and clinical disease. Hypersensitivity reactions are broadly categorized based on the kinetics of the response and the immunological mediators involved.
- Immediate Hypersensitivity
Manifests within minutes to hours of exposure in a sensitized host. It is primarily antibody-mediated (IgE, IgG, or IgM) and is classified into Types I, II, and III.
- Delayed-Type Hypersensitivity (DTH)
Manifests 2 to 3 days (48–72 hours) post-exposure. It is mediated by antigen-specific T lymphocytes (TH1 cells, and occasionally TC cells) and is classified as Type IV.
Classification at a Glance
Figure: Gell and Coombs Classification. Hypersensitivity splits by kinetics into immediate reactions (Types I–III, antibody-driven) and delayed reactions (Type IV, T-cell driven). Within the immediate branch, antibody-mediated responses further divide into IgE-driven Type I and IgG/IgM-driven Type II, while soluble immune complexes form the distinct Type III route.
Type I Hypersensitivity (Allergic / Anaphylactic)
Type I hypersensitivity is mediated by IgE-dependent humoral antibody responses. It is triggered by non-parasitic, environmental antigens known as allergens (e.g., pollens, foods, insect venom, animal dander).
Immunological Mechanism
- Sensitization Phase
Initial exposure to an allergen induces TH2 cell differentiation and subsequent B-cell class switching to IgE production.
- Mast Cell Arming
The secreted IgE binds with high affinity via its Fc region to FcεR (high-affinity IgE-specific Fc receptors) expressed on the surface of tissue mast cells and circulating basophils. The host is now sensitized.
- Re-exposure & Degranulation
Subsequent exposure to the same allergen leads to the cross-linking of IgE molecules bound to the FcεR. This activates intracellular signaling pathways, triggering the rapid fusion of secretory granules with the plasma membrane (degranulation) and releasing highly active chemical mediators.
Chemical Mediators of Type I Hypersensitivity
Primary Mediators — Pre-formed, Stored in Granules
- Histamine — increases vascular permeability, induces vasodilation and smooth muscle contraction.
- Proteases — degrade local extracellular matrix; activate tissue remodeling.
- Eosinophil Chemotactic Factor (ECF) — recruits eosinophils to the site of reaction.
- Neutrophil Chemotactic Factor (NCF) — recruits neutrophils to the site of reaction.
- Heparin — serves as a local anticoagulant.
Secondary Mediators — Synthesized De Novo from Membrane Lipids
- Prostaglandins & Leukotrienes — derived from arachidonic acid; induce prolonged bronchoconstriction, vascular permeability, and mucus secretion.
- Platelet-Activating Factor (PAF) — aggregates platelets; causes vasodilation and bronchoconstriction.
- Bradykinins — mediate vasodilation, smooth muscle contraction, and pain.
- Cytokines — drive chronic inflammatory cell recruitment and tissue remodeling.
Clinical Manifestations
- Anaphylaxis
A rapid, systemic, life-threatening allergic reaction, characterized by widespread vasodilation, severe bronchoconstriction, laryngeal edema, and systemic shock following re-exposure to an allergen (e.g., systemic penicillin administration or bee venom).
- Atopy
A hereditary, localized predisposition to develop Type I hypersensitivity reactions against common environmental substances. Examples include allergic rhinitis (hay fever), asthma, atopic dermatitis (eczema), and food allergies.
Type II Hypersensitivity (Antibody-Mediated Cytotoxic Reaction)
Type II hypersensitivity is characterized by antibodies (IgG or IgM) binding to specific antigens on host cell surfaces or extracellular matrix components, leading to the destruction of target host cells.
Two Primary Antibody-Mediated Mechanisms
- Complement-Mediated Lysis
IgG or IgM antibodies bind to cell-surface antigens and activate the classical complement pathway, culminating in cell lysis via assembly of the Membrane Attack Complex (MAC), or opsonization (via C3b and C4b) to enhance phagocytic uptake.
- Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)
IgG antibodies coat the target host cell. Natural Killer (NK) cells, monocytes, or neutrophils expressing surface Fcγ receptors bind to the Fc region of these antibodies, triggering the release of cytolytic perforins and granzymes and inducing target cell apoptosis without phagocytosis or complement fixation.
Figure: Type II Hypersensitivity Mechanisms. Both routes begin with antibody bound to a host cell surface antigen, then diverge — one activating classical complement toward MAC assembly or opsonization, the other recruiting FcγR-bearing NK cells for perforin/granzyme-driven apoptosis.
Classical Examples
- Incompatible Blood Transfusion
Host antibodies recognize donor erythrocyte ABO glycoprotein antigens, triggering immediate intravascular complement-mediated hemolysis.
- Erythroblastosis Fetalis
Hemolytic disease of the newborn: maternal IgG antibodies against the Rh antigen cross the placenta and target Rh-positive fetal red blood cells for destruction.
Type III Hypersensitivity (Immune Complex-Mediated)
Type III hypersensitivity is mediated by the accumulation of soluble antigen–antibody (immune) complexes in circulation.
Immunological Mechanism
- Normal Clearance
Under normal physiological conditions, large, particulate immune complexes are efficiently phagocytosed by macrophages in the spleen and liver.
- Deposition
In the presence of excess soluble antigens (or persistent infections), small, soluble immune complexes form, evade clearance, deposit in blood vessel walls or tissue structures (glomerular basement membranes, joint synovium, skin capillaries), and activate the classical complement pathway.
- Frustrated Phagocytosis
Complement activation releases chemotactic anaphylatoxins (C3a, C4a, C5a), recruiting neutrophils that cannot phagocytose the tissue-fixed complexes. They instead release tissue-damaging lysosomal enzymes, reactive oxygen species, and inflammatory cytokines.
Classical Examples
- Glomerulonephritis
Immune complex deposition along the renal glomerular basement membrane, causing kidney inflammation and damage.
- Arthritis
Immune complexes localized in joint synovium, triggering chronic joint inflammation.
Type IV Hypersensitivity (Delayed-Type / Cell-Mediated)
Type IV hypersensitivity is unique because it is entirely independent of antibodies. It is mediated by antigen-sensitized T lymphocytes (TH1 cells, and occasionally TC cells).
Immunological Mechanism
- Sensitization Phase
Antigens are captured and presented by local APCs to naïve helper T cells, driving their differentiation into antigen-specific TH1 cells.
- Effector Phase (Re-exposure)
Upon secondary antigen exposure, sensitized TH1 cells secrete inflammatory cytokines, primarily:
- IFN-γ (Interferon-gamma) — the primary activator of macrophages.
- TNF-β (Lymphotoxin) — induces local tissue damage and vascular endothelial changes.
- Macrophage Activation & Damage
Activated macrophages release lysosomal enzymes, reactive oxygen species, and reactive nitrogen species, causing localized cellular damage and tissue swelling. This reaction typically peaks 48 to 72 hours after antigen contact.
Diagnostic Example
The Tuberculin Skin Test (PPD Test)
Used to determine exposure to Mycobacterium tuberculosis. A small amount of Purified Protein Derivative (PPD) is injected intradermally. If the individual has been sensitized, memory TH1 cells recruit macrophages to the injection site, producing a firm, red induration (bump) within 48 hours.
2. Autoimmunity and the Breakdown of Tolerance
Autoimmunity is a condition in which host tissues suffer structural or functional damage due to an immunological attack launched by self-reactive, immunologically competent cells (T cells) or autoantibodies against self-antigens. It represents a fundamental failure of immune tolerance — the mechanism preventing host immune cells from reacting to self.
Molecular Triggers of Autoimmunity
Autoimmunity is initiated by a combination of genetic susceptibility and environmental triggers. Host defense mechanisms normally eliminate or silence self-reactive lymphocytes during development in the bone marrow and thymus (central tolerance) or in peripheral tissues (peripheral tolerance). This tolerance can break down through several key mechanisms.
Genetic Factors
- MHC Polymorphism
The strongest genetic link to autoimmune susceptibility resides within the Major Histocompatibility Complex (MHC) alleles. Certain MHC Class I or Class II alleles present self-peptides more efficiently to T cells, raising the risk of self-reactivity.
- Non-MHC Genes
Polymorphisms in genes regulating lymphocyte activation, cytokine signaling, or cell death pathways (e.g., CTLA4, PTPN22, FAS) also contribute.
Environmental & Microbial Triggers
- Molecular Mimicry
Structural similarities between microbial antigens and host self-antigens can lead to cross-reactive immune responses. For instance, antibodies raised against the M protein of Streptococcus pyogenes can cross-react with cardiac myosin, causing rheumatic heart disease.
- Enhanced Co-stimulator Expression
Viral or bacterial infections in peripheral tissues trigger local inflammation, leading to high-level expression of co-stimulatory ligands (CD80/CD86) on local APCs. If an APC displays a self-peptide alongside these co-stimulators, it can bypass peripheral anergy and activate a self-reactive T cell.
- Psycho-neuro-immunological Factors
Stress and neurochemicals can alter cytokine networks, indirectly modifying gene expression and compromising tolerance.
Classification of Autoimmune Diseases
Organ-Specific Autoimmune Diseases
The immune attack is directed against an antigen restricted to a single organ or gland.
Systemic (Non-Organ-Specific) Autoimmune Diseases
The immune attack is directed against widely distributed antigens, leading to multi-organ pathology.
Major Human Autoimmune Diseases
| Disease | Primary Target / Autoantigen | Classification | Pathophysiological Impact |
|---|---|---|---|
| Autoimmune Hemolytic Anemia | Rh erythrocyte antigen | Organ-Specific | Autoantibody binding to red blood cells triggers complement-mediated lysis or phagocytosis, causing severe anemia. |
| Graves’ Disease | Thyroid-Stimulating Hormone (TSH) Receptor | Organ-Specific | Autoantibodies bind to and chronically activate the TSH receptor, mimicking TSH and inducing hyperthyroidism. |
| Myasthenia Gravis | Acetylcholine Receptor (AChR) | Organ-Specific | Autoantibodies bind AChRs at the neuromuscular junction, blocking acetylcholine binding and inducing receptor degradation, causing progressive muscle weakness. |
| Type 1 Diabetes Mellitus | Pancreatic beta-cell antigens | Organ-Specific | Autoreactive CD8+ CTLs and TH1 cells selectively destroy insulin-producing beta cells in the islets of Langerhans, leading to insulin deficiency. |
| Multiple Sclerosis (MS) | Myelin Basic Protein (MBP) | Organ-Specific (CNS) | Autoreactive T cells infiltrate the central nervous system, causing inflammatory demyelination of nerve fibers. |
| Rheumatoid Arthritis (RA) | Unknown synovial joint antigen | Systemic | Chronic inflammatory destruction of joint cartilage and bone driven by autoreactive T cells, macrophages, and autoantibodies (Rheumatoid Factor). |
| Systemic Lupus Erythematosus (SLE) | Double-stranded DNA, histones, snRNP | Systemic | Production of antinuclear antibodies (ANAs) leads to systemic IgG–DNA immune complexes that deposit in the kidneys, joints, and skin, causing multi-organ vasculitis (Type III hypersensitivity). |
3. Transplantation Immunology and Graft Rejection
Transplantation is the process of transferring cells, tissues, or organs (grafts) from one individual (the donor) to another (the recipient or host). Blood transfusion represents a specialized form of fluid tissue transplantation.
Structural Terminology of Grafts
Grafts are classified based on the genetic relationship between the donor and recipient:
- Autograft (Autogeneic)
Tissue transplanted from one body site to another within the same individual (e.g., skin graft from thigh to arm). Fully accepted.
- Syngraft (Syngeneic / Isograft)
Tissue transplanted between genetically identical individuals of the same species (e.g., monozygotic twins or inbred mouse strains). Fully accepted.
- Allograft (Allogeneic)
Tissue transplanted between genetically different individuals of the same species (e.g., human-to-human kidney transplant). Expresses foreign histocompatibility antigens and is rejected unless immunosuppressive therapy is administered.
- Xenograft (Xenogeneic)
Tissue transplanted between individuals of different species (e.g., pig heart valve to human). Expresses highly foreign antigens and triggers the most rapid, aggressive rejection reactions.
Figure: Graft Classification by Genetic Relationship. Autografts and syngrafts share identical or near-identical genomes with the recipient and are fully accepted, while allografts express foreign histocompatibility antigens (alloantigens) and are rejected without immunosuppression.
The Molecular Basis of Alloreactivity
The molecules responsible for allograft rejection are called alloantigens.
- MHC Molecules
Serve as the primary alloantigens. Because MHC genes are highly polymorphic, two non-identical individuals will express distinct MHC Class I and Class II proteins. These foreign MHC molecules trigger a powerful T-cell response.
- Minor Histocompatibility Antigens
Polymorphic host cellular proteins other than MHC molecules. When presented as processed peptides on self-MHC molecules, they trigger a weaker, slower, and more gradual graft rejection response compared to major MHC mismatches.
Mechanisms of Alloantigen Recognition
Recipient T lymphocytes recognize donor alloantigens via two distinct pathways:
Direct Recognition
- Recipient T cells directly bind to intact foreign MHC molecules displayed on the surface of donor APCs (e.g., passenger dendritic cells residing within the graft) that have migrated to recipient lymph nodes.
- This pathway induces an exceptionally strong T-cell response because a high frequency of recipient T cells can bind directly to non-self MHC molecules.
Indirect Recognition
- Recipient APCs (dendritic cells and macrophages) enter the graft, phagocytose dead or damaged donor cells, and process the foreign MHC proteins into peptides.
- Processed peptides are presented on host self-MHC Class II molecules to host CD4+ helper T cells, resembling classical foreign antigen presentation.
Cross-Priming (Cross-Presentation)
Some endocytosed donor graft antigens enter the recipient APC's Class I pathway, allowing them to be presented to recipient CD8+ T cells as well.
Immunological Effector Mechanisms of Graft Rejection
Graft destruction is mediated by both cellular and humoral immune mechanisms:
- CD4+ T-cell Mediated Damage
Activated CD4+ helper T cells secrete IFN-γ and TNF-β to recruit and activate macrophages, driving a delayed-type hypersensitivity (DTH) response that causes widespread tissue damage and local microvascular inflammation.
- CD8+ T-cell Mediated Damage
Recipient CD8+ cytotoxic T lymphocytes (CTLs) directly recognize foreign MHC Class I molecules on parenchymal cells within the graft, releasing perforin and granzymes to induce target cell death. CD8+ CTLs generated via direct recognition are the most efficient killers of graft parenchymal cells — CD8+ T cells stimulated via the indirect pathway can only kill graft cells if recipient APCs present graft peptides directly.
- Antibody-Mediated Damage (Alloantibodies)
High-affinity alloantibodies (produced via helper T cell-dependent B-cell activation) target donor MHC Class I and Class II molecules on graft vascular endothelial cells. This activates classical complement cascade lysis, triggers ADCC via NK cells, and recruits neutrophils to the vascular lining.
Patterns of Graft Rejection
Allogeneic graft rejection reactions are classified into three clinical and pathological patterns based on their onset and underlying immunological mechanisms:
1. Hyperacute Rejection
Onset: Minutes to 24 Hours Post-Anastomosis
Mechanism
Mediated by pre-existing circulating host serum antibodies specific for donor antigens (e.g., anti-ABO or anti-MHC antibodies from prior blood transfusions, pregnancies, or transplants). These antibodies bind donor antigens on the graft's vascular endothelial cells, activating the classical complement cascade.
Pathology
Endothelial cell injury, neutrophil recruitment, platelet aggregation, and extensive intravascular thrombosis. This prevents graft vascularization, causing immediate tissue death.
2. Acute Rejection
Onset: Within the First Few Weeks Post-Transplant
Mechanism
Mediated by alloreactive T cells and antibodies activated post-transplantation, divided into two forms:
- Acute Cellular Rejection: Recipient CD4+ and CD8+ T cells damage the graft parenchyma and vascular endothelial cells through direct cytolysis and DTH cytokine-mediated inflammation.
- Acute Humoral Rejection: Alloreactive host antibodies bind to endothelial cells, inducing local complement-mediated lysis, neutrophil recruitment, and vascular thrombosis.
Pathology
Infiltration of mononuclear cells (lymphocytes and macrophages), endothelial cell swelling (endothelitis), and vascular lumen occlusion.
3. Chronic Rejection
Onset: Develops Slowly Over Months to Years
Mechanism
Driven by a chronic, low-grade humoral and cell-mediated immune response against the graft's vascular walls.
Pathology
Progressive fibrotic occlusion of the graft's arterial blood vessels (arteriosclerosis) and loss of functional parenchyma, leading to gradual organ failure.
Xenogeneic Transplantation (Xenotransplantation)
Xenotransplantation is the transfer of organs across species barriers (e.g., pig to human).
- Primary Immunological Barrier
Xenogeneic grafts are typically destroyed by hyperacute rejection, mediated by naturally occurring pre-existing antibodies in the human host that bind to carbohydrates expressed on the xenogeneic endothelial cell surface.
- Secondary Barriers
Even if hyperacute rejection is avoided (e.g., using genetically modified pigs lacking these carbohydrates), xenografts remain susceptible to a rapid, aggressive vascular rejection within 2 to 3 days, termed delayed xenograft rejection.
4. Immunodeficiency Diseases
Immunodeficiencies occur when one or more components of the host immune system are defective, rendering the host highly susceptible to recurrent microbial infections.
- Primary (Congenital) Immunodeficiency
Caused by genetic defects in genes regulating immune cell development, receptor assembly, or intracellular signaling. These are typically inherited.
- Secondary (Acquired) Immunodeficiency
Acquired post-birth due to extrinsic factors such as viral infections (e.g., HIV/AIDS), severe malnutrition, medical therapies (chemotherapy or immunosuppression), or aging.
Key Primary Immunodeficiency Syndromes
1. Severe Combined Immunodeficiency (SCID)
SCID is a heterogeneous group of genetic disorders characterized by a profound deficiency of both functional B and T lymphocytes. Affected infants fail to develop immunological memory or functional humoral and cellular immunity, leading to fatal opportunistic infections within the first year of life unless treated with hematopoietic stem cell transplantation.
- X-Linked SCID
The most common form of SCID. Caused by mutations in the gene encoding the common cytokine receptor gamma chain (γc), a shared subunit of the cell-surface receptors for IL-2, IL-4, IL-7, IL-9, and IL-15. Because IL-7 signaling is essential for early T-cell survival and development, T-cell maturation is completely blocked.
- Adenosine Deaminase (ADA) Deficiency
An autosomal recessive form of SCID. ADA is a critical enzyme in the purine salvage pathway that catalyzes the conversion of adenosine to inosine. A deficiency leads to accumulation of toxic purine metabolites (such as dATP) inside rapidly dividing cells, which are highly toxic to developing thymocytes and pre-B cells, halting lymphocyte development.
Figure: Two Molecular Routes to SCID. X-linked SCID disrupts γc-dependent interleukin signaling and blocks T-cell maturation directly, while ADA deficiency poisons dividing lymphocyte precursors with toxic purine metabolites — both converge on the same profound loss of functional B and T cells.
2. Chediak-Higashi Syndrome
An autosomal recessive immunodeficiency characterized by recurrent bacterial infections, oculocutaneous albinism (lack of skin and eye pigment), and neurological abnormalities.
- Molecular Defect
Mutations in a gene regulating vesicular fusion and intracellular protein trafficking (such as the LYST gene). This defect impairs the targeting of lysosomal proteins to lysosomes.
- Pathology
Phagocytic cells (neutrophils and macrophages) develop giant lysosomal granules because vesicles fail to divide properly. These phagocytes cannot kill ingested bacteria because their giant granules cannot fuse effectively with phagosomes, preventing normal phagolysosome formation. Functional NK cells are also absent or severely compromised due to defective cytolytic granule transport.
3. DiGeorge Syndrome (Congenital Thymic Aplasia)
A congenital disorder that is typically non-hereditary, occurring sporadically due to a microdeletion on chromosome 22 (22q11.2).
- Developmental Defect
Disrupts the normal embryonic migration of neural crest cells into the third and fourth pharyngeal pouches, which normally develop into the thymus and parathyroid glands.
- Immunological Manifestations
Complete or partial absence of the thymus leads to a profound deficiency of mature T lymphocytes and a complete lack of T-cell-dependent immune responses. While B-cell numbers are typically normal, patients cannot produce antibodies in response to immunization because they lack CD4+ T helper cells to drive B-cell activation.
- Non-Immunological Features
Hypoparathyroidism (causing severe hypocalcemia and tetany) and congenital cardiovascular defects.
5. Failures of Host Defense: Pathogen Immune Evasion
Pathogens and their hosts have co-evolved in an immunological arms race. To survive and multiply, successful pathogens have developed highly sophisticated strategies to avoid, subvert, or resist host immune responses.
Evasion of Adaptive Immune Humoral Responses
1. Antigenic Variation and Serotypes
Pathogens escape antibody-mediated neutralization by altering their surface molecules.
- Serotypes
Some pathogens exist in many distinct antigenic strains, known as serotypes, based on differences in their surface polysaccharide capsules or outer membrane proteins. For example, Streptococcus pneumoniae has over 90 distinct serotypes. An antibody response generated against one serotype provides no protective immunity against another.
2. Antigenic Drift and Antigenic Shift
This dynamic mechanism of antigenic variation is classically illustrated by the Influenza virus:
Antigenic Drift — Point Mutations
- Occurs when point mutations accumulate in the viral genes encoding hemagglutinin (HA) and neuraminidase (NA).
- Gradual accumulation; minor changes in HA/NA.
- Slowly alters the epitopes recognized by host neutralizing antibodies, allowing the virus to reinfect individuals immune to previous strains.
- Causes seasonal epidemics.
Antigenic Shift — Genomic Reassortment
- A sudden, dramatic change when two different influenza strains co-infect a single host cell (e.g., in a pig or bird).
- The segmented RNA genomes of the two strains undergo reassortment during viral assembly, producing a novel virus with entirely new HA or NA combinations.
- Because the human population lacks pre-existing immunity to this new combination, antigenic shift often triggers global pandemics.
3. Programmed Genomic DNA Rearrangement (Trypanosoma brucei)
Trypanosoma brucei, the protozoan parasite responsible for African sleeping sickness, utilizes a highly complex genetic mechanism to continuously alter its major outer coat, which consists of a single glycoprotein called the Variable Surface Glycoprotein (VSG).
- The VSG Reservoir
The T. brucei genome contains approximately 1000 distinct VSG genes, but only a single VSG gene is expressed at any given time because it must reside within an active expression site near the chromosome telomere.
- Gene Duplication & Transposition
The active VSG gene is periodically replaced by copying an inactive VSG gene from the genomic reservoir and transposing it into the active expression site, altering the parasite's surface coat.
- Mechanistic Cycle
When the host mounts a highly specific neutralizing antibody response against the dominant VSG, it clears most parasites. A small subpopulation undergoes genomic rearrangement, switching expression to a different VSG gene, escaping antibody clearance and multiplying — causing a recurrent wave of parasitemia and a chronic, undulating infection.
Resistance to Intracellular Destruction Following Phagocytosis
Many intracellular pathogens avoid destruction by manipulating host cellular machinery inside macrophages and neutrophils:
Figure: Three Strategies for Intracellular Survival. Pathogens either block phagolysosome fusion outright, rupture the phagosomal membrane to escape into the cytosol, or tolerate the fused phagolysosome by resisting its acidic, enzyme-rich environment.
- Prevention of Phagolysosome Fusion
After being phagocytosed into a vesicle (the phagosome), some pathogens actively block fusion of this phagosome with cellular lysosomes, preventing delivery of acidic hydrolases and microbicidal enzymes.
- Mycobacterium tuberculosis
- Salmonella enterica
- Legionella pneumophila
- Escape from the Phagosome into the Cytosol
Some pathogens secrete proteins that degrade or rupture the phagosomal membrane shortly after internalization, allowing escape into the nutrient-rich, neutral-pH cytosol before lysosomal fusion can occur.
- Listeria monocytogenes — secretes listeriolysin O, a pore-forming toxin that disrupts the phagosomal membrane.
- Trypanosoma cruzi
- Survival Within the Host Phagolysosome
Some highly resilient pathogens allow phagolysosome fusion to proceed normally but possess specialized structural coats or defense systems that resist low pH, hydrolytic enzymes, and reactive chemical species.
- Coxiella burnetii
- Leishmania parasites
6. Vaccine Biology and Technology
A vaccine is a non-toxic, immunogenic preparation containing microbial antigens that is administered to induce protective, long-term, antigen-specific adaptive immunity (antibodies and memory B/T cells) against a pathogen without causing the clinical disease. The process of administering a vaccine is vaccination, and the physiological induction of an immune response is immunization (representing artificial active immunity).
- Herd Immunity
Occurs when a high proportion of individuals within a community are immunized against a specific infectious disease. This reduces the chain of transmission, making it highly difficult for a pathogen to spread and indirectly protecting unimmunized, vulnerable individuals (such as newborns or immunocompromised patients).
Structural Classifications of Vaccines
1. Whole-Organism Vaccines
These vaccines contain the complete pathogen, rendered harmless through attenuation or inactivation:
Live But Attenuated Vaccines
The pathogen is weakened (attenuated) by growing it sequentially in unfavorable laboratory conditions (e.g., in non-human host cells or low temperatures) over many passages, accumulating mutations that eliminate its pathogenicity while preserving its immunogenicity.
- Example: The Sabin oral polio vaccine (three attenuated strains of poliovirus) and the BCG vaccine for tuberculosis.
Inactivated (Killed) Vaccines
The pathogen is killed or inactivated using heat or chemical treatment (such as formaldehyde or alkylating agents) to ensure it cannot multiply, while carefully maintaining the structural integrity of its surface epitopes.
- Example: The Salk polio vaccine (administered via injection).
Comparative Evaluation: Attenuated vs. Inactivated Vaccines
| Vaccine Attribute | Live Attenuated Vaccine | Inactivated (Killed) Vaccine |
|---|---|---|
| Booster Dose Requirements | Generally requires a single booster dose. | Requires multiple booster doses to maintain protective immunity. |
| Relative Stability | Less stable; requires a strictly maintained cold chain. | Highly stable; more resistant to temperature fluctuations. |
| Immunity Induced | Stimulates both robust humoral (antibody) and cell-mediated (T-cell) immunity. | Stimulates primarily humoral (antibody) immunity. |
| Reversion to Virulent Form | Small risk of reverting to a virulent, disease-causing wild-type form via back-mutations. | Cannot revert to a virulent form. |
2. Purified Antigen (Subunit) Vaccines
Rather than administering the entire pathogen, subunit vaccines utilize specific, purified immunogenic macromolecules:
- Toxoids
Inactivated bacterial exotoxins. Many pathogenic bacteria cause disease primarily by secreting toxins; these exotoxins are purified and chemically modified (often using formaldehyde) to eliminate toxicity while preserving antigenic structure. Diphtheria and tetanus vaccines are produced as toxoids.
- Capsular Polysaccharides
Composed of purified bacterial polysaccharide capsules (e.g., from Streptococcus pneumoniae or Neisseria meningitidis). Limitation: these molecules act as Thymus-Independent type 2 (TI-2) antigens, activating mature B cells directly without T-cell help. This induces only short-lived IgM production with little to no isotype class switching, no affinity maturation, and no memory cell generation.
- Conjugate Vaccines
Developed to overcome the limitations of capsular polysaccharide vaccines. A purified bacterial polysaccharide antigen is covalently attached (conjugated) to a strong immunogenic protein carrier (such as a tetanus or diphtheria toxoid protein), recruiting T-cell help and transforming a thymus-independent response into a thymus-dependent one.
Figure: Conjugate Vaccine Mechanism. Attaching a polysaccharide antigen to a protein carrier lets the B cell recruit CD4+ T-cell help, converting a thymus-independent response into a thymus-dependent one that drives class switching, affinity maturation, and memory formation.
- Recombinant Subunit Vaccines
Produced by cloning the gene encoding a highly immunogenic surface antigen of a pathogen into an expression vector and expressing it in recombinant host cells (yeast, bacteria, or mammalian cells). The purified antigen, being a soluble protein, is processed via the exogenous MHC Class II pathway, inducing robust humoral immunity. Example: the Hepatitis B vaccine, produced by expressing HBsAg in recombinant yeast cells.
3. DNA Vaccines (Genetic Vaccines)
DNA vaccines represent a modern molecular approach to immunization:
- Immunological Principle
A plasmid vector containing the gene for a highly immunogenic pathogen protein (driven by a strong eukaryotic promoter) is injected directly into host tissue (usually muscle). Host cells take up the plasmid, transcribe the gene, and translate it, expressing the foreign protein intracellularly.
- Antigen Presentation
Because the antigen is synthesized inside the host cell, it is processed through the endogenous pathway and presented on MHC Class I molecules, triggering a strong CD8+ CTL response. Some protein is also secreted or released upon host cell apoptosis, allowing capture by local APCs and presentation on MHC Class II to CD4+ T helper cells, triggering a robust humoral antibody response.
4. Recombinant Vector Vaccines
Recombinant vector vaccines combine the high immunogenicity of live attenuated vaccines with the safety of subunit vaccines:
- Immunological Principle
Genes encoding highly immunogenic antigens isolated from a pathogen are inserted into the genome of a non-virulent or attenuated virus or bacterium (the vector), such as vaccinia virus, adenovirus, or canary pox virus.
- Mechanism
The recombinant vector infects host cells but cannot cause disease. As it replicates, it expresses the pathogen-encoded antigen inside the host cells, presenting it via both MHC Class I and Class II pathways to stimulate robust cell-mediated and humoral immunity.
Common Human Vaccines for Infectious Diseases
| Disease | Vaccine Type Administered |
|---|---|
| Bacterial Diseases | |
| Anthrax | Toxoid |
| Diphtheria | Toxoid |
| Tetanus | Toxoid |
| Pertussis | Killed bacteria (Bordetella pertussis) or acellular proteins |
| Typhoid Fever | Killed bacteria (Salmonella typhi) |
| Tuberculosis | Attenuated strain of Mycobacterium bovis (BCG vaccine) |
| Meningitis | Purified polysaccharide from Neisseria meningitidis |
| Bacterial Pneumonia | Purified polysaccharide from Streptococcus pneumoniae |
| Viral Diseases | |
| Measles | Attenuated virus |
| Mumps | Attenuated virus |
| Rubella | Attenuated virus |
| Varicella (Chickenpox) | Attenuated virus |
| Polio | Attenuated virus (Sabin) or Inactivated virus (Salk) |
| Influenza | Inactivated virus |
| Rabies | Inactivated virus |
| Smallpox | Cross-reacting live virus (Vaccinia) |
| Hepatitis B | Recombinant DNA vaccine (HBsAg expressed in yeast) or inactivated virus |
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LessonStep 26 of 28
