Immunology
1. What this chapter covers, and how NEET PG actually tests it
Immunology is often learned as an inventory of cells, molecules and abbreviations with no evident structure.
One division organises almost all of it: the innate system is fast, fixed and identical every time, while the adaptive system is slow, specific and improves with repetition.
Everything follows from that trade-off. Speed requires pre-existing recognition molecules, which means limited variety. Specificity requires generating new receptors, which takes days.
The whole architecture of vaccination, of recurrent infection, and of immunodeficiency presentation follows from where a defect sits on that axis.
| Property | Innate | Adaptive |
|---|---|---|
| Speed | Minutes to hours | Days |
| Specificity | Broad patterns | Precise antigens |
| Memory | None | Yes |
| Recognition | Pattern recognition receptors | Rearranged receptors |
| Components | Barriers, phagocytes, complement, NK cells | T cells, B cells, antibody |
2. Innate immunity
2.1 Recognition without specificity
Innate recognition depends on pattern recognition receptors detecting molecular signatures shared by broad classes of pathogen.
Toll-like receptors are the principal family, and each recognises a conserved structure: lipopolysaccharide, flagellin, peptidoglycan, or viral nucleic acid.
These targets are conserved precisely because a pathogen cannot discard them without losing viability, which is why innate recognition remains effective despite never adapting.
Recognition triggers cytokine release, and the acute phase response follows: fever from interleukin-1 and interleukin-6, and hepatic synthesis of C-reactive protein and other acute phase proteins.
2.2 The cellular and humoral arms
Neutrophils arrive first and dominate acute bacterial infection; macrophages arrive later, phagocytose, and present antigen to T cells.
Natural killer cells are the exception that recognises absence: they kill cells that have lost MHC class I.
That mechanism exists because viruses and tumours frequently downregulate MHC class I to escape cytotoxic T cells, so natural killer cells close exactly the gap that evasion opens.
Complement is activated by three pathways: classical by antibody, alternative by microbial surfaces, and lectin by mannose, all converging on C3.
C3b opsonises, C3a and C5a are anaphylatoxins with C5a also chemotactic, and C5 to C9 form the membrane attack complex.
The membrane attack complex is the only mechanism that effectively kills Neisseria, which is why terminal complement deficiency produces narrowly neisserial susceptibility.
3. Adaptive immunity
3.1 Generating diversity
Antibody and T cell receptor diversity comes from somatic recombination of variable, diversity and joining gene segments, with additional junctional variation.
A limited number of gene segments recombined in different combinations generates a receptor repertoire far larger than the genome could otherwise encode.
Somatic hypermutation occurs later, in germinal centres, and refines affinity after antigen exposure, which is why a secondary response produces better antibody as well as more of it.
Class switching changes the constant region while preserving specificity, so the same antibody can be redeployed to a different effector function.
Both processes require CD40 ligand from T cells, which is why its absence produces hyper-IgM syndrome with normal IgM and low everything else.
3.2 Where lymphocytes are made and selected
B cells develop in the bone marrow and T cells in the thymus, which are the primary lymphoid organs.
Lymph nodes, spleen and mucosa-associated lymphoid tissue are secondary organs, where lymphocytes meet antigen.
Thymic selection is a two-stage filter, and both stages are necessary.
Positive selection keeps thymocytes whose receptors can bind self-MHC at all, since a receptor that cannot engage MHC is useless.
Negative selection then deletes those binding self-peptide too strongly, which is what prevents autoimmunity.
That second stage depends on the AIRE gene, which allows thymic epithelium to display tissue-specific antigens from all over the body.
AIRE mutation causes autoimmune polyendocrine syndrome type 1, and it demonstrates that central tolerance is an active process rather than a passive absence of self-antigen.
Only around two per cent of thymocytes survive both filters, which is the price of a repertoire that is both functional and self-tolerant.
3.3 The cytokines worth knowing
| Cytokine | Principal action |
|---|---|
| IL-1 | Fever, endothelial activation |
| IL-2 | T cell proliferation |
| IL-4 | Th2 differentiation, IgE class switching |
| IL-5 | Eosinophil growth and activation |
| IL-6 | Acute phase protein synthesis, fever |
| IL-8 | Neutrophil chemotaxis |
| IL-10 | Anti-inflammatory, suppression |
| IL-12 | Th1 differentiation, NK activation |
| TNF-alpha | Fever, cachexia, granuloma maintenance |
| Interferon-gamma | Macrophage activation |
| Interferons alpha and beta | Antiviral state in neighbouring cells |
Interferons alpha and beta do not kill viruses directly; they induce an antiviral state in surrounding uninfected cells, which is why they limit spread rather than clearing established infection.
Interleukin-1, interleukin-6 and TNF-alpha are the three principal pyrogens, and blocking them is how several biologic therapies work.
3.4 Antigen presentation and T cells
MHC class I is present on all nucleated cells, presents endogenous antigen, and is recognised by CD8 cells.
MHC class II is present on antigen-presenting cells, presents exogenous antigen, and is recognised by CD4 cells.
The rule of eight is a reliable memory aid: class I times CD8 equals eight, class II times CD4 equals eight.
T cell activation requires two signals: antigen with MHC, and costimulation through CD28 binding B7.
Antigen without costimulation produces anergy rather than activation, which is one mechanism of peripheral tolerance.
CTLA-4 competes with CD28 for B7 and delivers an inhibitory signal, which is the brake that checkpoint inhibitors release.
3.5 The helper subsets
| Subset | Signature cytokines | Function |
|---|---|---|
| Th1 | Interferon-gamma | Macrophage activation, intracellular organisms |
| Th2 | IL-4, IL-5, IL-13 | IgE, eosinophils, helminths |
| Th17 | IL-17 | Neutrophil recruitment, extracellular bacteria and fungi |
| Treg | IL-10, TGF-beta | Suppression, tolerance |
Th1 and Th2 cross-inhibit, which is why the balance between them determines whether a response is granulomatous or allergic.
Interleukin-12 from macrophages drives Th1 differentiation, and the Th1 axis is what maintains granulomas.
Treg cells express FOXP3, and its mutation causes IPEX syndrome with severe multi-organ autoimmunity in infancy.
4. Antibody, vaccines and transplantation
4.1 The immunoglobulin classes
| Class | Key feature |
|---|---|
| IgG | Most abundant, only class crossing the placenta, four subclasses |
| IgM | First produced, pentameric, best complement activator |
| IgA | Mucosal, dimeric with secretory component, in breast milk |
| IgE | Mast cell binding, allergy and helminths |
| IgD | Naive B cell surface, function uncertain |
IgM is the best complement activator because it is pentameric, so a single bound molecule presents multiple Fc regions and satisfies the requirement for C1q to bind two adjacent sites.
IgG requires two molecules bound close together to achieve the same thing, which is why it is a less efficient complement fixer despite being more abundant.
The secretory component protects IgA from proteolysis in the gut lumen, which is what allows it to function outside the body.
Transplacental IgG protects the infant for roughly six months, which is why antibody deficiencies declare themselves at that age.
4.2 Vaccines
| Type | Examples | Properties |
|---|---|---|
| Live attenuated | BCG, MMR, oral polio, varicella | Strong, lasting, cell-mediated; avoid in immunosuppression and pregnancy |
| Inactivated | Injectable polio, rabies, hepatitis A | Safe, needs boosters |
| Subunit or conjugate | Hepatitis B, Hib, pneumococcal conjugate | Safe, conjugation adds T cell help |
| Toxoid | Tetanus, diphtheria | Neutralises toxin, not organism |
| mRNA and viral vector | COVID-19 vaccines | Rapid development, strong response |
Conjugating a polysaccharide to a protein converts a T-independent response into a T-dependent one, which is why conjugate vaccines work in infants under two while plain polysaccharide vaccines do not.
That single mechanism explains the dramatic fall in invasive Haemophilus influenzae type b disease after conjugate vaccination.
Live vaccines are avoided in pregnancy and significant immunosuppression because the attenuated organism can still replicate.
Passive immunisation with preformed antibody gives immediate but temporary protection, and is used in post-exposure prophylaxis alongside active vaccination.
Rabies post-exposure prophylaxis illustrates why both are given together: the immunoglobulin protects during the days before the vaccine generates a response, and the vaccine then provides durable protection the immunoglobulin cannot.
The two must be injected at separate sites, since antibody at the vaccine site would neutralise the vaccine antigen before it could stimulate a response.
Herd immunity thresholds vary with transmissibility, which is why measles requires around ninety-five per cent coverage while less transmissible diseases require considerably less.
4.3 India's Universal Immunisation Programme
The national schedule is examined directly, and the timings follow immunological logic rather than convenience.
| Age | Vaccines |
|---|---|
| Birth | BCG, oral polio zero dose, hepatitis B birth dose |
| 6, 10, 14 weeks | Pentavalent, oral polio, rotavirus, pneumococcal conjugate, injectable polio |
| 9 to 12 months | Measles-rubella first dose, JE where endemic, vitamin A |
| 16 to 24 months | Measles-rubella second dose, DPT booster, oral polio booster, JE second dose |
| 5 to 6 years | DPT second booster |
| 10 and 16 years | Tetanus and adult diphtheria |
Measles vaccine is deferred to nine months because maternal antibody would otherwise neutralise the live vaccine virus, and giving it earlier produces poor seroconversion.
That same maternal antibody is why the birth dose of hepatitis B works differently: it is given immediately precisely to pre-empt perinatal transmission.
The three primary doses at six, ten and fourteen weeks reflect the need for repeated exposure to generate memory in an immature immune system.
BCG is given at birth because tuberculosis exposure in India begins early and the vaccine protects best against disseminated childhood disease rather than adult pulmonary tuberculosis.
4.4 Transplantation
Hyperacute rejection occurs within minutes from preformed antibody; acute cellular rejection over days to months; chronic rejection over years as vascular fibrosis.
Graft-versus-host disease requires an immunocompetent graft and an immunocompromised host, which is why it complicates bone marrow rather than solid organ transplantation.
HLA matching matters most for bone marrow transplantation, and blood group compatibility must also be respected.
The privileged sites — cornea, brain, testis and anterior chamber of the eye — tolerate grafts unusually well because of physical barriers and local immunosuppressive mediators.
That privilege is what makes corneal grafting possible without systemic immunosuppression or tissue matching.
5. Immunodeficiency, autoimmunity and diagnostics
5.1 Reading the infection pattern
The organisms causing trouble identify the failed arm, because each arm defends against a different class of pathogen.
Encapsulated bacteria from six months indicate antibody deficiency; opportunists from birth indicate T cell deficiency; catalase-positive organisms indicate a phagocyte defect; recurrent Neisseria indicates terminal complement deficiency.
Age at onset and organism type should agree, and when they do the diagnosis is usually secure without genetic testing.
Human immunodeficiency virus depletes CD4 cells, and the CD4 count predicts which opportunistic infections become possible, which is why prophylaxis thresholds are defined by that count.
5.2 The classical serological reactions
Serology is examined through the physical form the reaction takes, and each form suits a different type of antigen.
Precipitation occurs when antibody meets soluble antigen; agglutination occurs when antibody meets particulate antigen.
That distinction explains why the same antibody produces a visible line in a gel against a soluble protein but visible clumping against whole cells.
Precipitation reactions are maximal at the zone of equivalence, where antigen and antibody are in balanced proportion.
Excess of either antigen or antibody inhibits lattice formation, which is the prozone phenomenon and a well-recognised cause of a falsely negative VDRL in secondary syphilis with very high titres.
Diluting the serum restores the result, which is why an unexpectedly negative test in a clinically obvious case should prompt repeat testing at dilution.
Complement fixation tests detect antibody indirectly by measuring complement consumption, and are now largely historical.
Immunofluorescence localises antigen in tissue and comes in direct form, using labelled antibody against the target, and indirect form, using an unlabelled primary and a labelled secondary antibody.
The indirect method is more sensitive because several labelled secondary antibodies bind each primary, amplifying the signal.
5.3 Modern diagnostic methods
ELISA detects antigen or antibody with high sensitivity and is the usual screening method.
Western blot separates proteins by size before detection and was historically the confirmatory test for HIV.
Flow cytometry counts cells by surface marker, which is how CD4 counts and paroxysmal nocturnal haemoglobinuria diagnosis are performed.
Polymerase chain reaction detects nucleic acid and is the most sensitive method, detecting infection before antibody appears.
The window period in HIV exists because antibody takes weeks to appear, which is why nucleic acid testing closes it and why blood banks use it.
6. Worked examples
Example 1
Why does the plain pneumococcal polysaccharide vaccine fail in infants under two while the conjugate vaccine works?
Polysaccharide antigens cross-link B cell receptors directly and stimulate antibody without T cell help.
That T-independent response is weak, produces no class switching and no memory, and the immature infant immune system mounts it poorly.
Conjugating the polysaccharide to a carrier protein means T cells recognise the protein and provide help, converting the response to a T-dependent one with class switching, affinity maturation and memory.
This is why conjugate vaccines protect infants and generate herd immunity by reducing nasopharyngeal carriage.
Example 2
A boy has recurrent bacterial infections. IgM is raised while IgG, IgA and IgE are all low, and B cells are present.
The presence of B cells excludes a developmental block such as Bruton agammaglobulinaemia, which would abolish all classes.
Producing IgM but nothing else localises the fault precisely to class switching.
Class switching requires CD40 ligand on T cells engaging CD40 on B cells, so its absence gives exactly this pattern.
The immunoglobulin profile alone identifies hyper-IgM syndrome without any genetic test.
Example 3
A virus downregulates MHC class I on infected cells to avoid cytotoxic T cells. Why does this not guarantee escape?
Cytotoxic CD8 cells require MHC class I to recognise their target, so losing it does defeat them.
Natural killer cells work on the opposite rule, killing cells that lack MHC class I rather than cells that display foreign peptide on it.
A virus that hides from T cells therefore exposes itself to natural killer cells, which is why the two systems together leave no straightforward escape route.
The same logic applies to tumours, and it is one reason natural killer cells are of interest in cancer immunotherapy.
7. Traps the exam sets repeatedly
Assuming IgG is the best complement activator. IgM is, because pentameric structure allows a single molecule to bind C1q.
Giving a live vaccine in significant immunosuppression or pregnancy. The attenuated organism can still replicate.
Expecting an infant antibody deficiency to present at birth. Maternal IgG protects for about six months.
Reading a negative HIV antibody test as excluding infection. The window period requires nucleic acid testing to close.
Treating anergy as the same thing as deletion. Anergy is unresponsiveness after antigen without costimulation, and is a peripheral rather than central mechanism.
Accepting a negative VDRL at face value in florid secondary syphilis. The prozone phenomenon from antibody excess can make it falsely negative until the serum is diluted.
Giving measles vaccine before nine months routinely. Maternal antibody neutralises the live virus and seroconversion is poor.
Assuming interferons alpha and beta kill viruses. They induce an antiviral state in neighbouring uninfected cells and limit spread.
Summary
The innate system trades specificity for speed, and the adaptive system trades speed for specificity and memory.
Pattern recognition receptors target conserved structures a pathogen cannot discard, which is why innate immunity remains effective without adapting.
Natural killer cells kill cells lacking MHC class I, closing exactly the gap that viral and tumour evasion opens.
Somatic recombination generates a repertoire larger than the genome could encode, and somatic hypermutation refines it after exposure.
MHC class I presents endogenous antigen to CD8 cells and class II presents exogenous antigen to CD4 cells.
T cell activation needs antigen plus costimulation; antigen alone produces anergy.
IgM is pentameric and therefore the best complement activator, while IgG alone crosses the placenta.
Conjugating a polysaccharide to protein converts a T-independent response into a T-dependent one, which is why conjugate vaccines work in infants.
The organism pattern and age at onset together identify which immune arm has failed.
Thymic selection is a two-stage filter, and AIRE-dependent negative selection is what prevents autoimmunity.
Precipitation needs soluble antigen and agglutination needs particulate antigen, with the prozone phenomenon causing false negatives at antibody excess.
Measles vaccine is deferred to nine months because maternal antibody would neutralise the live virus.
Nucleic acid testing closes the antibody window period, which is why blood banks rely on it.
