Immune Response

Innate Immunity

Innate immunity is the immediate, germline-encoded defence system that recognises conserved microbial or danger-associated molecular patterns and generates inflammation, phagocytosis, cytotoxicity and early antiviral states. It operates within minutes to hours, does not require clonal expansion, and has limited specificity compared with adaptive immunity; however, it instructs adaptive responses through antigen presentation, cytokine polarisation and co-stimulation.

Recognition: pattern-recognition receptors

Innate immune cells recognise pathogen-associated molecular patterns and damage-associated molecular patterns using pattern-recognition receptors. These receptors are non-polymorphic within individuals and detect structures essential to pathogens, limiting immune escape.

Receptor family	Principal location	Key ligands	Major downstream effect
Toll-like receptors	Cell surface or endosome	TLR4: lipopolysaccharide; TLR2: peptidoglycan/lipoproteins; TLR3: dsRNA; TLR7/8: ssRNA; TLR9: CpG DNA	NF-κB and interferon-regulatory factor activation; TNF, IL-1, IL-6, type I interferons
NOD-like receptors	Cytosol	Bacterial peptidoglycan fragments; cellular stress signals	NF-κB activation; inflammasome assembly
RIG-I-like receptors	Cytosol	Viral RNA	Type I interferon induction
cGAS-STING pathway	Cytosol/endoplasmic reticulum	Cytosolic DNA	Type I interferons; antiviral and antitumour innate responses
C-type lectin receptors	Cell surface	Fungal carbohydrates including β-glucans and mannans	Phagocytosis and antifungal cytokine responses

The NLRP3 inflammasome is particularly exam-relevant: diverse triggers such as urate crystals, cholesterol crystals, silica, asbestos and ATP promote caspase-1 activation, generating mature IL-1β and IL-18 and inducing pyroptotic cell death. This underpins gout, some autoinflammatory syndromes and the rationale for IL-1 blockade in selected conditions.

Effector cells and mechanisms

Neutrophils are the dominant acute bacterial and fungal effector cells. Normal adult neutrophil count is approximately 2.0-7.5 × 10⁹/L; clinically important neutropenia is usually <1.5 × 10⁹/L, severe at <0.5 × 10⁹/L, and profound at <0.1 × 10⁹/L. Neutrophil recruitment follows rolling mediated by selectins, firm adhesion via integrins binding ICAM-1/VCAM-1, diapedesis, and chemotaxis along gradients such as IL-8, C5a, leukotriene B4 and bacterial N-formyl peptides.

Microbial killing requires phagocytosis, phagolysosomal fusion, acidification, antimicrobial granule proteins and the respiratory burst. NADPH oxidase generates superoxide, which is converted to hydrogen peroxide; myeloperoxidase uses hydrogen peroxide and chloride to produce hypochlorous acid. Defects produce characteristic phenotypes: chronic granulomatous disease causes catalase-positive bacterial and fungal infections with abnormal dihydrorhodamine testing; myeloperoxidase deficiency is often mild but predisposes to Candida in some patients; leukocyte adhesion deficiency causes delayed umbilical separation, marked neutrophilia and absent pus formation.

Macrophages derive from circulating monocytes and tissue-resident lineages. They phagocytose opsonised material, produce TNF, IL-1, IL-6, IL-12 and chemokines, and orchestrate granulomatous inflammation. Classically activated macrophages are induced by microbial products and interferon-γ, promoting intracellular killing; alternatively activated macrophages are associated with IL-4/IL-13-driven repair, fibrosis and helminth responses.

Dendritic cells bridge innate and adaptive immunity. Conventional dendritic cells ingest antigen in tissues and migrate to lymph nodes after activation; plasmacytoid dendritic cells produce large amounts of type I interferon during viral infection. Although antigen presentation is an adaptive immune requirement, the decision to provide co-stimulation is primarily innate and depends on danger recognition.

Natural killer cells provide early defence against virally infected and malignant cells. They integrate activating signals with inhibitory receptors recognising self-MHC class I. Loss or downregulation of MHC class I, common in viral immune evasion and malignancy, favours NK-cell cytotoxicity via perforin-granzyme release. NK cells also mediate antibody-dependent cellular cytotoxicity through CD16 binding to IgG Fc, and produce interferon-γ to activate macrophages.

Barriers, acute-phase response and clinical interpretation

Epithelial barriers provide mechanical exclusion, tight junctions, mucociliary clearance, gastric acid, bile salts, defensins, lysozyme, lactoferrin and a competitive microbiota. Breaches from neutropenia, burns, central venous catheters, urinary catheters or corticosteroids increase infection risk by compromising different innate layers.

The systemic acute-phase response is driven mainly by IL-1, TNF and IL-6. Hepatic synthesis of C-reactive protein, serum amyloid A, fibrinogen, hepcidin and complement components increases, while albumin and transferrin fall. CRP is typically <5 mg/L in health, rises within 6-8 hours, peaks at approximately 48 hours, and has a plasma half-life of about 19 hours; persistent elevation therefore usually reflects ongoing stimulus rather than slow clearance. Procalcitonin is often used to support bacterial infection assessment, with values <0.25 microgram/L arguing against bacterial lower respiratory infection in many algorithms and >0.5 microgram/L supporting systemic bacterial infection, though renal failure, trauma and major surgery reduce specificity.

For MRCP, innate immunity is best understood as a layered system: barrier exclusion, rapid recognition, vascular inflammation, cellular recruitment, microbial killing, and immune instruction. Recurrent severe bacterial or fungal infection from early life, poor pus formation, unusual catalase-positive organisms, delayed wound healing or exaggerated autoinflammation should prompt consideration of a primary innate immune defect.

Adaptive Immunity

Core principles and phases

Adaptive immunity is antigen-specific, clonally distributed and generates immunological memory. It is mediated by lymphocytes bearing somatically recombined antigen receptors: the B-cell receptor/immunoglobulin and the T-cell receptor. Diversity is generated by V(D)J recombination via RAG1/RAG2, junctional diversity mediated by terminal deoxynucleotidyl transferase, and combinatorial pairing; the theoretical TCR repertoire exceeds 10¹⁵, although the realised circulating repertoire is smaller. Unlike innate immunity, adaptive responses require clonal selection and expansion, explaining the delay in primary responses.

1. Antigen capture and presentation: protein antigens are processed by antigen-presenting cells and displayed on major histocompatibility complex molecules. MHC class I presents endogenous peptides to CD8⁺ T cells; MHC class II presents exogenous peptides to CD4⁺ T cells.
2. Naïve lymphocyte activation: requires antigen recognition plus co-stimulation. For T cells, signal 1 is TCR–peptide–MHC recognition; signal 2 is typically CD28–B7. Absence of co-stimulation promotes anergy or deletion.
3. Clonal expansion and differentiation: IL-2-driven proliferation is central for T cells; B cells undergo germinal-centre reactions with class-switch recombination and somatic hypermutation.
4. Effector phase and contraction: effector cells clear antigen, followed by apoptosis of most expanded clones; a minority persist as memory cells.

T-cell immunity

Naïve T cells mature in the thymus, where positive selection preserves cells able to recognise self-MHC and negative selection deletes high-affinity self-reactive clones; AIRE-dependent expression of tissue-restricted antigens is critical. Failure predisposes to autoimmunity, as in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

T-cell subset	Defining features	Principal function	Exam relevance
CD4+ Th1	T-bet; IFN-γ predominant	Macrophage activation; intracellular pathogens	Granulomatous inflammation; mycobacterial susceptibility if defective
CD4+ Th2	GATA-3; IL-4, IL-5, IL-13	IgE class switching; eosinophil responses	Atopy, asthma, helminth immunity
CD4+ Th17	RORγt; IL-17/IL-22 axis	Neutrophil recruitment; mucocutaneous defence	Chronic mucocutaneous candidiasis; psoriasis biology
Treg	CD4+CD25highFOXP3+	Peripheral tolerance; suppresses autoreactive lymphocytes	FOXP3 mutation causes IPEX syndrome
CD8+ cytotoxic T cell	MHC I restricted	Perforin/granzyme-mediated apoptosis; Fas–FasL killing	Viral control; malignancy immunosurveillance

Normal adult CD4 count is approximately 500–1500 cells/µL, with a CD4:CD8 ratio around 1.5–2.5:1. In HIV, a CD4 count below 200 cells/µL is a key threshold for Pneumocystis jirovecii pneumonia risk and prophylaxis, illustrating the clinical importance of cell-mediated immunity.

B-cell immunity and antibody responses

B cells develop in bone marrow and undergo central tolerance by deletion, anergy or receptor editing. Following antigen encounter, T-dependent responses require CD40–CD40L interaction; CD40L deficiency causes the X-linked hyper-IgM phenotype with impaired class switching. In germinal centres, activation-induced cytidine deaminase mediates class-switch recombination and somatic hypermutation, producing high-affinity plasma cells and memory B cells. Primary antibody responses typically generate detectable IgM after 5–7 days, peak at 10–14 days, and later switch to IgG, IgA or IgE. Secondary responses occur within 1–3 days, are higher affinity, and are predominantly class-switched.

Immunoglobulin	Key properties	Approximate serum half-life
IgG	Major serum antibody; opsonisation; placental transfer via FcRn; secondary response	21 days
IgA	Mucosal and secretory immunity; dimeric form in secretions	6 days
IgM	First antibody in primary response; pentameric; strong agglutination	5 days
IgE	Mast-cell and basophil FcεRI binding; allergy and helminths	2 days in serum; longer when cell-bound
IgD	Naïve B-cell receptor with IgM	About 3 days

Memory, tolerance and therapeutic manipulation

Adaptive memory explains durable vaccine protection and more rapid secondary responses. Live attenuated vaccines usually generate broader cellular and humoral immunity but are contraindicated in severe T-cell immunodeficiency; polysaccharide vaccines are T-independent and perform poorly in children under 2 years, whereas conjugation to protein recruits T-cell help and improves memory.

Peripheral tolerance depends on anergy, deletion, immune privilege and active suppression by Tregs. Checkpoint pathways such as CTLA-4 and PD-1 restrain T-cell activation; blockade with ipilimumab, nivolumab or pembrolizumab enhances anti-tumour immunity but causes immune-related adverse events including colitis, hepatitis, endocrinopathies and pneumonitis. Conversely, immunosuppressive therapies exploit adaptive mechanisms: ciclosporin and tacrolimus inhibit calcineurin-dependent IL-2 transcription; mycophenolate inhibits inosine monophosphate dehydrogenase, preferentially impairing lymphocyte purine synthesis; rituximab depletes CD20⁺ B cells but not plasma cells, explaining preserved existing antibody titres with impaired new humoral responses.

Cytokines

Cytokines are low-molecular-weight, soluble or membrane-bound proteins that coordinate immune cell activation, differentiation, trafficking and effector function. They act predominantly via paracrine and autocrine signalling, with endocrine effects in systemic inflammation. Key exam principles are pleiotropy (one cytokine, multiple effects), redundancy (overlapping functions), synergy, antagonism and cascade induction. Their plasma half-lives are usually short, often minutes, because biological potency depends on receptor expression and local concentration rather than sustained systemic levels.

Classification and signalling

Group	Examples	Principal signalling	High-yield functions
Interleukins	IL-1, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-17, IL-23	JAK-STAT, NF-κB, MAPK depending on receptor family	T-cell polarisation, fever, B-cell help, acute phase response
Interferons	Type I: IFN-α, IFN-β; Type II: IFN-γ; Type III: IFN-λ	JAK-STAT with interferon-stimulated gene transcription	Antiviral state, macrophage activation, HLA upregulation
Tumour necrosis factor family	TNF-α, lymphotoxin, Fas ligand, CD40L	TNFR-associated factors, NF-κB; death domains for apoptosis	Endothelial activation, granuloma maintenance, septic shock biology
Chemokines	CCL2, CCL5, CXCL8/IL-8, CXCL10	G-protein-coupled receptors	Leucocyte chemotaxis; CXCL8 recruits neutrophils
Haematopoietic growth factors	GM-CSF, G-CSF, M-CSF, IL-3, erythropoietin	JAK-STAT and related pathways	Myeloid proliferation, emergency granulopoiesis

Most cytokine receptors fall into conserved families. Type I cytokine receptors include receptors for IL-2, IL-4, IL-6, IL-7, IL-12 and GM-CSF; many use JAK1/JAK3 or JAK2/TYK2. The common γ-chain is shared by IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 receptors; mutation causes X-linked severe combined immunodeficiency. Type II receptors bind interferons and IL-10 family cytokines. IL-1 family receptors signal via MyD88 and NF-κB, mechanistically resembling Toll-like receptor pathways.

Functional cytokine networks

IL-1, TNF-α and IL-6 dominate early systemic inflammation. IL-1 and TNF-α induce fever via hypothalamic prostaglandin E₂, increase endothelial adhesion molecules and vascular permeability, and promote leukocyte recruitment. IL-6 drives hepatocyte acute phase protein synthesis, especially CRP, fibrinogen and hepcidin; it also promotes thrombocytosis and anaemia of inflammation. CRP typically rises within 6–8 hours, peaks at about 48 hours and has a half-life of approximately 19 hours, making it a useful downstream biomarker rather than a cytokine assay.

T-cell polarisation is cytokine-defined. IL-12 and IFN-γ promote Th1 differentiation, supporting macrophage activation and intracellular pathogen control. IL-4 drives Th2 differentiation, class-switching to IgE and eosinophilic inflammation with IL-5 and IL-13. IL-6, IL-1β, TGF-β and IL-23 favour Th17 responses; IL-17 recruits neutrophils and is central in psoriasis, axial spondyloarthritis and mucocutaneous candidiasis susceptibility. IL-10 and TGF-β are regulatory cytokines limiting antigen-presenting cell activation and effector T-cell responses.

Clinical syndromes and diagnostic relevance

Cytokine biology underlies fever, sepsis, macrophage activation syndrome and cytokine release syndrome. In sepsis, excessive TNF-α, IL-1β and IL-6 contribute to vasodilatation, capillary leak, myocardial depression and disseminated endothelial activation, but anti-cytokine monotherapy has largely failed because timing, redundancy and host heterogeneity are critical. IL-6 concentrations may be markedly elevated in severe inflammation; reference intervals are assay-dependent, commonly quoted as less than 5–7 pg/mL in healthy adults, while severe COVID-19, HLH or cytokine release syndrome may show tens to thousands of pg/mL.

Secondary haemophagocytic lymphohistiocytosis/macrophage activation syndrome reflects uncontrolled activation of macrophages and cytotoxic T cells with high IFN-γ, IL-1, IL-6, IL-18 and soluble IL-2 receptor. Exam clues include persistent fever, splenomegaly, cytopenias, hepatitis, coagulopathy, hypertriglyceridaemia and very high ferritin; ferritin >10,000 µg/L is highly suggestive in children, though less specific in adults. HLH-2004 criteria require 5 of 8 features, including ferritin ≥500 µg/L, triglycerides ≥3.0 mmol/L and/or fibrinogen ≤1.5 g/L, low NK-cell activity, haemophagocytosis and elevated soluble CD25.

Therapeutic manipulation of cytokines

Target	Agent examples	Typical adult regimen	Major exam adverse effects
TNF-α	Infliximab, adalimumab, etanercept	Infliximab 5 mg/kg IV at weeks 0, 2, 6 then 8-weekly; adalimumab 40 mg SC every 2 weeks	TB/hepatitis B reactivation, demyelination, heart failure worsening, lupus-like syndrome
IL-6 receptor	Tocilizumab, sarilumab	Tocilizumab 8 mg/kg IV 4-weekly in RA; in COVID-19 8 mg/kg IV once, maximum 800 mg	Neutropenia, raised transaminases, hyperlipidaemia, bowel perforation risk; CRP suppression masks infection
IL-1	Anakinra, canakinumab	Anakinra 100 mg SC daily; dose reduce in severe renal impairment	Injection reactions, neutropenia, infection; useful in autoinflammatory disease and MAS
IL-17/IL-23 axis	Secukinumab, ixekizumab, ustekinumab, guselkumab	Regimens vary by indication; usually SC loading then 4–12-weekly maintenance	Mucocutaneous candidiasis with IL-17 blockade; avoid IL-17 inhibitors in active IBD
JAK pathways	Tofacitinib, baricitinib, upadacitinib	Tofacitinib 5 mg orally twice daily; baricitinib 2–4 mg daily depending on indication/renal function	Herpes zoster, cytopenias, venous thromboembolism signal, lipid rise, serious infection
G-CSF	Filgrastim, pegfilgrastim	Filgrastim 5 micrograms/kg/day SC; pegfilgrastim 6 mg SC once per chemotherapy cycle	Bone pain, leukocytosis, splenic rupture rarely

Landmark evidence illustrates context-specific benefit. The RECOVERY trial showed that tocilizumab reduced 28-day mortality in hospitalised hypoxic COVID-19 patients with systemic inflammation, typically CRP ≥75 mg/L, when added to standard care including corticosteroids. Conversely, broad anti-TNF or anti-IL-1 strategies in unselected sepsis did not deliver reproducible survival benefit, reinforcing that cytokines are network nodes rather than isolated linear mediators.

Complement

Complement is a liver-derived, plasma and membrane-associated proteolytic cascade linking innate recognition to inflammation, opsonisation, immune complex clearance and direct microbial lysis. Most components circulate as inactive zymogens; activation is amplified on biological surfaces and constrained on host cells by soluble and membrane regulators. For MRCP, the high-yield framework is: trigger → C3 convertase → C5 convertase → terminal complement complex, with clinical disease arising from deficiency, dysregulation or therapeutic blockade.

Activation pathways and effector mechanisms

Pathway	Trigger	C3 convertase	Key associations
Classical	C1q binding to IgM or clustered IgG1/IgG3 immune complexes; also CRP	C4b2a	Immune complex disease; SLE activity; early component deficiency
Lectin	MBL or ficolins binding microbial mannose/N-acetylglucosamine; MASP-1/2 activation	C4b2a	Recurrent childhood infection in MBL deficiency, usually mild
Alternative	Spontaneous C3 “tick-over” and amplification on poorly regulated surfaces	C3bBb, stabilised by properdin	Neisseria risk; atypical HUS; C3 glomerulopathy

All pathways converge on cleavage of C3 into C3a and C3b. C3b covalently deposits via its thioester bond, opsonising pathogens and forming C5 convertases: C4b2a3b or C3bBb3b. Cleavage of C5 generates C5a, a potent anaphylatoxin and neutrophil chemoattractant, and C5b, which nucleates assembly of C5b-9, the membrane attack complex. C3b and iC3b promote phagocytosis through complement receptors CR1, CR3 and CR4; C3d lowers the threshold for B-cell activation via CR2/CD21, explaining complement’s bridge to adaptive immunity. C3a, C4a and especially C5a increase vascular permeability, mast-cell degranulation and leukocyte activation.

Regulation

Complement activation is limited by fluid-phase and membrane regulators. C1 inhibitor blocks C1r/C1s and MASPs and also regulates contact pathway proteases; deficiency causes bradykinin-mediated hereditary angio-oedema rather than histamine-mediated urticaria. Factor H and factor I inactivate C3b, aided by host sialic acid; abnormalities predispose to atypical haemolytic uraemic syndrome and C3 glomerulopathy. DAF/CD55 accelerates convertase decay and CD59 prevents C9 polymerisation. Loss of GPI-anchored CD55/CD59 in paroxysmal nocturnal haemoglobinuria produces complement-mediated intravascular haemolysis.

Laboratory interpretation

Complement tests are pattern-recognition tools rather than standalone diagnoses. Typical adult reference ranges vary by laboratory: C3 approximately 0.75–1.65 g/L, C4 approximately 0.14–0.54 g/L. CH50 screens classical/terminal pathway integrity; AH50 screens the alternative pathway. Low CH50 with normal AH50 suggests early classical component deficiency; absent CH50 and AH50 suggests C3 or terminal pathway deficiency; low AH50 with preserved CH50 suggests alternative pathway defects such as properdin or factor D deficiency. In active immune complex SLE, C3 and C4 fall and anti-dsDNA often rises; isolated low C4 is typical of C1 inhibitor deficiency or classical pathway activation.

Complement abnormality	Characteristic clinical phenotype	Exam clue
C1q, C1r/s, C2, C4 deficiency	SLE-like disease, immune complex disease, infections with encapsulated organisms	Early classical defects strongly associated with lupus
C3 deficiency	Severe recurrent pyogenic infection, immune complex disease	Most clinically severe central complement deficiency
C5-C9 deficiency	Recurrent Neisseria meningitidis or gonococcal infection	Terminal pathway defects; vaccinate and consider prophylaxis
Properdin deficiency	Fulminant meningococcaemia, X-linked pattern	Alternative pathway stabiliser
C1 inhibitor deficiency/dysfunction	Hereditary angio-oedema: swelling, abdominal pain, laryngeal oedema, no urticaria	Low C4; type I has low C1-INH level, type II normal/high level but low function

Complement-targeted therapies

Complement blockade is now central in PNH, atypical HUS and selected neuromyelitis optica spectrum disorder, and increasingly in renal disease. Because C5 inhibition predisposes to meningococcal infection, patients require MenACWY and MenB vaccination ideally at least 2 weeks before treatment; urgent therapy should not be delayed, but antibiotic prophylaxis is commonly used according to local policy.

Drug	Target and use	Adult dosing commonly examined
Eculizumab	Monoclonal antibody to C5; PNH, atypical HUS, refractory generalised myasthenia gravis, AQP4-positive NMOSD	PNH: 600 mg IV weekly for 4 weeks, 900 mg week 5, then 900 mg every 2 weeks
Ravulizumab	Long-acting C5 inhibitor; same principle as eculizumab	Weight-based IV loading then maintenance every 8 weeks; terminal half-life about 50 days
C1 inhibitor concentrate	Acute hereditary angio-oedema and peri-procedural prophylaxis	Plasma-derived C1-INH often 20 units/kg IV for acute attacks
Icatibant	Bradykinin B2 receptor antagonist for hereditary angio-oedema	30 mg subcutaneously; may repeat at 6-hour intervals, maximum 3 doses/24 h

Landmark PNH evidence includes the TRIUMPH trial, in which eculizumab reduced haemolysis, transfusion requirements and fatigue compared with placebo, establishing C5 blockade as disease-modifying rather than merely supportive. Clinically, persistent anaemia on C5 inhibition may reflect extravascular haemolysis from C3 fragment opsonisation, breakthrough terminal activation, iron deficiency, marrow failure or thrombosis. The essential exam principle is that complement is beneficial when locally activated on microbes but pathological when activation escapes regulation, deposits on host endothelium, or is therapeutically suppressed without appropriate infection prevention.