Clinical Immunology: Immune system basics and immunological investigations

🛡️ Immune system basics and immunological investigations - page 1 of the Clinical Immunology chapter. Clinical immunology covers immunodeficiency, allergy, autoimmunity and the drugs that manipulate the immune system. Every doctor meets these problems - recurrent infections, anaphylaxis, positive autoantibodies, patients on biologics. This page covers the parts of the immune system that matter clinically and the tests used to examine them.
Your four questions for every immunology problem: Is the immune system underactive (infection), overactive (allergy, autoimmunity, inflammation) or misdirected? Which arm is involved - innate, antibody, T cell or complement? Which test answers the question? Could a drug be the cause?

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Overview - Innate and Adaptive Immunity

• Innate immunity - rapid (minutes to hours), non-specific, no memory: barriers (skin, mucosa), neutrophils, macrophages, NK cells, complement, pattern recognition receptors (Toll-like receptors), acute phase proteins.
• Adaptive immunity - slower (days), highly specific, memory: T cells (cell-mediated) and B cells (antibodies).
• The two arms work together - dendritic cells link innate to adaptive immunity by presenting antigen to T cells; antibodies activate complement and help phagocytes.
• Primary lymphoid organs - bone marrow (B-cell development) and thymus (T-cell development and selection).
• Secondary lymphoid organs - lymph nodes, spleen (filters blood - removes encapsulated bacteria and damaged red cells), mucosa-associated lymphoid tissue (tonsils, Peyer's patches).
• Clinical pattern of infection points to the defect:
  • Antibody - recurrent bacterial sinopulmonary infections with encapsulated organisms (pneumococcus, Haemophilus), bronchiectasis, giardia, enteroviruses.
  • T cell - viral (CMV, VZV), fungal (candida, Pneumocystis), mycobacterial infections; failure to thrive in infants.
  • Neutrophil - skin and deep abscesses, Staphylococcus aureus, Gram-negative bacteria, Aspergillus.
  • Complement - Neisseria (late components), pyogenic infection (C3), lupus-like disease (early components).

Innate Immunity

• Barriers - skin, mucous membranes, cilia, gastric acid, commensal flora, antimicrobial peptides (defensins), lysozyme. Breaches - burns, IV lines, catheters, mucositis, broad-spectrum antibiotics.
• Neutrophils - the most numerous white cell; first to arrive at infection; phagocytose and kill with the respiratory burst (NADPH oxidase - defective in chronic granulomatous disease), enzymes and neutrophil extracellular traps; short life (hours to days).
• Monocytes and macrophages - phagocytosis, antigen presentation, cytokine production (IL-1, IL-6, TNF); tissue macrophages - Kupffer cells (liver), alveolar macrophages, microglia, osteoclasts.
• Dendritic cells - the main antigen-presenting cells - carry antigen from tissues to lymph nodes to activate naive T cells.
• Natural killer (NK) cells - kill virus-infected and tumour cells that have lost MHC class I ("missing self"); antibody-dependent cellular cytotoxicity.
• Mast cells and basophils - IgE receptors; release histamine, tryptase, leukotrienes and prostaglandins - allergy and anaphylaxis.
• Eosinophils - parasites (helminths) and allergic inflammation (asthma, EGPA, eosinophilic oesophagitis).
• Pattern recognition receptors - recognise microbial molecules (e.g. lipopolysaccharide via TLR4) - trigger inflammation; overactivation contributes to sepsis.
• Acute phase response - IL-6 drives the liver to produce CRP, fibrinogen, ferritin, complement and serum amyloid A; albumin falls.

The Complement System

• A cascade of over 30 plasma proteins (mostly made in the liver) - kills microbes, opsonises them for phagocytosis, drives inflammation and clears immune complexes.
• Three pathways, all converging on C3:
  • Classical - triggered by antibody–antigen complexes (IgG, IgM) binding C1q → C4 and C2.
  • Lectin - mannose-binding lectin binds microbial sugars.
  • Alternative - spontaneous C3 activation on microbial surfaces (factors B, D, properdin).
• Functions:
  • Opsonisation - C3b coats microbes.
  • Inflammation - C3a and C5a (anaphylatoxins) recruit neutrophils.
  • Membrane attack complex - C5b–C9 punches holes in bacterial membranes - vital against Neisseria.
  • Immune complex clearance - early components (C1q, C2, C4) - deficiency causes lupus-like disease.
• Regulators - C1 inhibitor (deficient in hereditary angioedema), factor H and factor I (deficient in atypical HUS and C3 glomerulopathy), CD55 and CD59 (lost in paroxysmal nocturnal haemoglobinuria).
• Therapeutic complement blockade - eculizumab and ravulizumab (anti-C5 - PNH, aHUS, myasthenia gravis, NMOSD) - high risk of meningococcal infection (vaccinate and give prophylactic antibiotics).

T Cells and Cell-mediated Immunity

• T cells develop in the thymus - positive selection (recognise self-MHC) and negative selection (delete strongly self-reactive cells - central tolerance; AIRE gene).
• CD4+ helper T cells - recognise antigen on MHC class II; coordinate the immune response by releasing cytokines:
  • Th1 - IFN-γ - activates macrophages - intracellular pathogens (mycobacteria); granulomas; type IV hypersensitivity.
  • Th2 - IL-4, IL-5, IL-13 - IgE, eosinophils - parasites, allergy, asthma (targets for dupilumab, mepolizumab).
  • Th17 - IL-17 - neutrophils - extracellular bacteria and fungi (candida); psoriasis, spondyloarthritis.
  • T follicular helper - help B cells make high-affinity antibodies.
  • Regulatory T cells (Tregs) - FOXP3 - suppress immune responses (peripheral tolerance; IPEX syndrome when absent).
• CD8+ cytotoxic T cells - recognise antigen on MHC class I (all nucleated cells) - kill virus-infected and tumour cells (perforin, granzymes).
• T-cell activation needs two signals - antigen–MHC (signal 1) and co-stimulation (CD28 binding CD80/86 - signal 2); checkpoints (CTLA-4, PD-1) switch T cells off - the targets of checkpoint inhibitor cancer drugs (see page 6).
• HIV infects CD4+ T cells - CD4 count predicts opportunistic infection risk (PCP under 200).
• Drugs acting on T cells - calcineurin inhibitors (tacrolimus, ciclosporin - block IL-2), corticosteroids, abatacept (blocks co-stimulation), anti-thymocyte globulin.

B Cells and Antibodies

• B cells mature in the bone marrow; on meeting antigen (with T-cell help) they become plasma cells that secrete antibody, and memory B cells.
• Antibody structure - two heavy and two light (kappa or lambda) chains; Fab binds antigen; Fc binds complement and Fc receptors on immune cells.
• Immunoglobulin classes:

  Class	Key features
  IgG	Most abundant (about 75%); four subclasses; crosses the placenta (passive protection for newborns for 3–6 months); opsonises; activates complement; secondary response; long half-life (about 3 weeks)
  IgM	Pentamer; first antibody made in a primary response (acute infection serology); strong complement activation; doesn't cross the placenta (raised in the newborn suggests congenital infection)
  IgA	Dimer in secretions (gut, airways, breast milk) - mucosal defence; selective IgA deficiency is the commonest immunodeficiency
  IgE	Binds mast cells and basophils - allergy and parasite defence; very low levels normally
  IgD	On naive B cells; function unclear

• Class switching (IgM → IgG, IgA, IgE) needs CD40 ligand on T cells - absent in X-linked hyper-IgM syndrome.
• Responses - protein antigens are T-dependent (memory, boostable); polysaccharide antigens (pneumococcal capsule) are T-independent - poor responses under age 2 (hence conjugate vaccines).
• Monoclonal immunoglobulin (paraprotein) - a single plasma cell clone - MGUS, myeloma, Waldenström macroglobulinaemia, AL amyloidosis.

Cytokines and Inflammation

• Cytokines - signalling proteins that coordinate immunity; many are now drug targets:

  Cytokine	Main effects	Blocked by
  TNF-α	Inflammation, fever, cachexia, granuloma maintenance	Infliximab, adalimumab, etanercept
  IL-1	Fever, inflammation - autoinflammatory diseases, gout	Anakinra, canakinumab
  IL-6	Acute phase response (CRP), fever	Tocilizumab, sarilumab
  IL-17	Neutrophil recruitment - psoriasis, spondyloarthritis	Secukinumab, ixekizumab
  IL-12/IL-23	Th1 and Th17 differentiation	Ustekinumab; IL-23 - risankizumab, guselkumab
  IL-4 and IL-13	IgE class switching, Th2 inflammation	Dupilumab
  IL-5	Eosinophil production and survival	Mepolizumab, benralizumab (receptor)
  IFN-γ	Macrophage activation - mycobacterial defence	Emapalumab (HLH)
  IL-2	T-cell proliferation	Tacrolimus, ciclosporin (reduce production); basiliximab (receptor)

• JAK–STAT pathway - many cytokine receptors signal through Janus kinases - JAK inhibitors (tofacitinib, baricitinib, upadacitinib) block several cytokines at once.
• Cytokine storm - excessive cytokine release - sepsis, haemophagocytic lymphohistiocytosis, CAR-T cell therapy (cytokine release syndrome - tocilizumab), severe COVID-19.
• Autoinflammatory diseases - innate immune overactivity without autoantibodies - periodic fevers (e.g. familial Mediterranean fever - colchicine; CAPS - IL-1 blockade), adult-onset Still's disease, VEXAS syndrome (older men - fevers, chondritis, macrocytosis).

HLA, Antigen Presentation and Tolerance

• HLA (human leucocyte antigen) - the human MHC on chromosome 6; very polymorphic; inherited as haplotypes (siblings have a 1 in 4 chance of being an HLA-identical match).
  • Class I (HLA-A, B, C) - on all nucleated cells - present intracellular (e.g. viral) peptides to CD8+ T cells.
  • Class II (HLA-DR, DQ, DP) - on antigen-presenting cells - present extracellular antigens to CD4+ T cells.
• Clinical importance:
  • Transplantation - HLA matching and antibodies (see page 6).
  • Disease associations - HLA-B27 (ankylosing spondylitis, reactive arthritis, anterior uveitis), HLA-DQ2/DQ8 (coeliac disease), HLA-DR4 (rheumatoid arthritis), HLA-DR3 (type 1 diabetes, Graves', SLE), HLA-B51 (Behçet's), HLA-DR15 (multiple sclerosis, Goodpasture's), HLA-B*58:01 (allopurinol reactions), HLA-B*57:01 (abacavir hypersensitivity).
• Tolerance - the immune system normally doesn't attack self:
  • Central - deletion of self-reactive T cells in the thymus and B cells in the bone marrow.
  • Peripheral - regulatory T cells, anergy (no co-stimulation), checkpoint molecules.
• Breakdown of tolerance → autoimmunity - genetic susceptibility (HLA and many other genes), environment (infection - molecular mimicry, smoking, drugs, UV light), female sex, and checkpoint inhibitor therapy (see page 5).

Hypersensitivity Reactions (Gell and Coombs)

Type	Mechanism	Timing	Examples
I - immediate	IgE on mast cells → histamine and mediators	Minutes	Anaphylaxis, urticaria, allergic rhinitis, asthma, food and venom allergy
II - cytotoxic	IgG or IgM against cell-surface or tissue antigens	Hours–days	Autoimmune haemolytic anaemia, ITP, haemolytic transfusion reactions, haemolytic disease of the newborn, Goodpasture's (anti-GBM), myasthenia gravis and Graves' (receptor antibodies - sometimes called type V), pemphigus
III - immune complex	Antigen–antibody complexes deposit and activate complement	Hours–days (1–3 weeks for serum sickness)	SLE, post-streptococcal GN, serum sickness, cryoglobulinaemic vasculitis, hypersensitivity pneumonitis (partly), Arthus reaction
IV - delayed	T cells and macrophages	48–72 hours	Contact dermatitis (nickel), tuberculin (Mantoux) test, granulomas (TB, sarcoidosis), type 1 diabetes, transplant rejection, severe drug reactions (SJS/TEN, DRESS)

• Non-IgE (non-allergic) mast cell activation - e.g. opioids, vancomycin ("red man" or vancomycin flushing syndrome - infusion-rate related), radiocontrast, NSAIDs, MRGPRX2-mediated reactions (some neuromuscular blockers, fluoroquinolones) - can cause anaphylaxis clinically identical to IgE-mediated.

First-line Immunology Tests

• For suspected immunodeficiency (recurrent, severe, unusual or persistent infection):
  • FBC with differential - neutropenia, lymphopenia (T-cell defect - SCID in infants, HIV), thrombocytopenia with small platelets (Wiskott–Aldrich), Howell–Jolly bodies (hyposplenism).
  • Serum immunoglobulins (IgG, IgA, IgM) and protein electrophoresis.
  • HIV test - always.
  • Renal and liver function, albumin, urine protein - for protein loss (nephrotic syndrome, protein-losing enteropathy).
  • Specific antibody (vaccine) responses - tetanus, Hib, pneumococcal serotypes; repeat 4–6 weeks after test immunisation if low.
• Second line (immunology advice) - lymphocyte subsets, complement function, neutrophil oxidative burst, genetic testing.
• For suspected autoimmunity - targeted autoantibodies guided by clinical features (see page 5), complement C3 and C4, CRP and ESR, urine dipstick for blood and protein.
• For suspected allergy - clinical history first; then skin prick tests, specific IgE, mast cell tryptase after a reaction (see page 4).
• Interpreting tests - no test replaces the history; avoid "screening" autoantibody panels without clinical suspicion (false positives are common).

Immunoglobulins and Protein Electrophoresis

• Low immunoglobulins (hypogammaglobulinaemia):
  • Primary - CVID, X-linked agammaglobulinaemia, selective IgA deficiency (IgA only), hyper-IgM (low IgG and IgA, normal or high IgM).
  • Secondary (much more common) - drugs (rituximab and other anti-CD20s, corticosteroids, antiepileptics - carbamazepine, phenytoin, mycophenolate), haematological cancers (CLL, myeloma - low "background" immunoglobulins, lymphoma), protein loss (nephrotic syndrome, protein-losing enteropathy, burns), CAR-T therapy.
• High immunoglobulins:
  • Polyclonal (broad band) - chronic infection (HIV, hepatitis, TB, endocarditis), liver disease (IgA in alcohol; IgG in autoimmune hepatitis; IgM in PBC), autoimmune disease (Sjögren's, SLE), sarcoidosis, IgG4-related disease (raised IgG4).
  • Monoclonal (narrow band - paraprotein) - MGUS, myeloma, Waldenström's (IgM), AL amyloidosis, lymphoma, CLL - check serum free light chains and urine Bence Jones protein.
• Raised total IgE - atopy (eczema, asthma), parasites, ABPA (very high), hyper-IgE syndrome, EGPA, some lymphomas; total IgE alone doesn't diagnose allergy.
• IgG subclasses - limited value alone; interpret with specific antibody responses.
• Paraprotein clue - high total protein with low albumin, raised calcium, anaemia, renal impairment, bone pain.

Lymphocyte Subsets and Functional Tests

• Lymphocyte subsets (flow cytometry):
  • CD3 (all T cells), CD4 (helper), CD8 (cytotoxic), CD19 or CD20 (B cells), CD16/56 (NK cells).
  • Uses - SCID (absent T cells), XLA (absent B cells), HIV (CD4 count), monitoring after rituximab (B-cell depletion), CVID (memory B cells), lymphoproliferative disease.
  • Note - infants have much higher normal lymphocyte counts; use age-related ranges (a "normal adult" count may be lymphopenic for a baby).
• Neutrophil function - dihydrorhodamine (DHR) flow cytometry (respiratory burst) for chronic granulomatous disease (replaced the nitroblue tetrazolium test); CD18 expression for leukocyte adhesion deficiency.
• T-cell function - proliferation to mitogens and antigens; TREC (T-cell receptor excision circles - newborn SCID screening).
• Interferon-gamma release assays (IGRA) - QuantiFERON, T-SPOT.TB - latent TB screening (before biologics, transplant); may be falsely negative in severe immunosuppression.
• NK function and perforin - haemophagocytic lymphohistiocytosis.
• Genetic testing - inborn errors of immunity gene panels or whole genome sequencing.

Complement Tests

• C3 and C4 (levels):
  • Both low - classical pathway activation - active SLE (especially lupus nephritis), cryoglobulinaemia, immune complex disease, MPGN, sepsis.
  • Low C4, normal C3 - hereditary angioedema (C1 inhibitor deficiency - C4 low even between attacks), cryoglobulinaemia, inherited C4 deficiency, early SLE.
  • Low C3, normal C4 - alternative pathway - post-streptococcal glomerulonephritis (recovers in 6–8 weeks), C3 glomerulopathy (C3 nephritic factor), atypical HUS, partial lipodystrophy.
• Functional tests - CH50 (classical pathway) and AP50 (alternative pathway) - screen for inherited complement deficiency (e.g. after recurrent or unusual Neisseria infection - meningococcal disease with an uncommon serogroup or in an adult); absent CH50 suggests a missing component.
• C1 inhibitor level and function - hereditary and acquired angioedema (see page 4).
• C1q - low in acquired angioedema (lymphoproliferative disease, autoantibodies) and inherited C1q deficiency (severe childhood SLE).
• Complement activation products and genetics (factor H, factor I, CD46) - atypical HUS.
• Sample handling - complement degrades quickly - send promptly to the lab.

CRP, ESR, Ferritin and Procalcitonin

• CRP - acute phase protein made in the liver in response to IL-6; rises within 6 hours, peaks at 48 hours, half-life about 19 hours - good for monitoring infection and inflammation.
  • Normal or only mildly raised CRP with a high ESR - classically in SLE (a high CRP in lupus suggests infection or serositis) and paraproteinaemia.
  • Tocilizumab and other IL-6 blockers suppress CRP - CRP may stay normal despite serious infection.
• ESR - rises more slowly; affected by fibrinogen, immunoglobulins (paraprotein), anaemia, age and sex; useful in giant cell arteritis, PMR, myeloma.
• Ferritin - acute phase reactant as well as iron store; very high (often over 10,000) in HLH, adult-onset Still's disease, macrophage activation syndrome, severe infection.
• Procalcitonin - rises in bacterial infection more than viral or non-infective inflammation - can guide stopping antibiotics (specific settings).
• White cell count - neutrophilia (bacterial infection, steroids, inflammation), lymphopenia (viral infection, steroids, SLE, HIV), eosinophilia (allergy, drugs, parasites, EGPA, Addison's, lymphoma).

Allergy Tests

• History is the most important allergy test - what, how much, how quickly, what happened, previous tolerance.
• Skin prick testing - drop of allergen pricked into the skin; a wheal (usually 3 mm or more above the negative control) at 15 minutes shows sensitisation (IgE). Positive (histamine) and negative (saline) controls; stop antihistamines for several days before.
• Specific IgE (blood) - useful when skin testing isn't possible (eczema, dermatographism, antihistamines); quantitative.
• Sensitisation is not allergy - positive tests are common in people without symptoms; interpret only alongside a convincing history.
• Component-resolved diagnostics - IgE to specific proteins - e.g. peanut Ara h 2 (predicts true peanut allergy and severe reactions) vs Ara h 8 (pollen cross-reactivity - usually mild oral symptoms).
• Intradermal tests - drug and venom allergy (specialist).
• Patch tests - type IV contact dermatitis (read at 48 and 96 hours).
• Challenge tests - oral food challenge or drug challenge (gold standard) under medical supervision.
• Mast cell tryptase - after a suspected anaphylaxis (see page 4).
• Unvalidated tests to avoid - IgG food antibody tests, vega testing, kinesiology, hair analysis.

Immunology Tests at a Glance

Test	Main use
FBC and film	Neutropenia, lymphopenia, small platelets, Howell–Jolly bodies
IgG, IgA, IgM	Antibody deficiency (low) or chronic inflammation (high)
Protein electrophoresis, free light chains	Paraprotein (myeloma, MGUS); hypogammaglobulinaemia
Vaccine responses	Functional antibody deficiency (CVID, specific antibody deficiency)
Lymphocyte subsets	SCID, XLA, HIV, post-rituximab
DHR test	Chronic granulomatous disease
C3 and C4	SLE activity, HAE (low C4), post-strep GN (low C3)
CH50 and AP50	Inherited complement deficiency (recurrent Neisseria)
C1 inhibitor level and function	Hereditary and acquired angioedema
Skin prick or specific IgE	Sensitisation in IgE-mediated allergy
Mast cell tryptase	Confirms anaphylaxis; raised baseline in mastocytosis
IGRA	Latent TB before biologics and transplant
Ferritin	Very high in HLH and Still's disease

Spot the Diagnosis

Clue	Diagnosis or defect
Recurrent pneumonia and sinusitis with bronchiectasis	Antibody deficiency
Recurrent skin abscesses and Aspergillus pneumonia in a boy	Neutrophil defect - chronic granulomatous disease
Two episodes of meningococcal meningitis in an adult	Late complement (C5–C9) deficiency - check CH50 and AP50
Recurrent swelling without urticaria; low C4 between attacks	Hereditary angioedema
Low C3 and C4, raised dsDNA and active nephritis	Active SLE
Low C3, normal C4, haematuria 2 weeks after sore throat	Post-streptococcal glomerulonephritis
High ESR with a normal CRP in a woman with arthralgia and rash	Consider SLE
Normal CRP despite sepsis in a patient on tocilizumab	IL-6 blockade suppresses CRP
Low IgG after rituximab with recurrent chest infections	Secondary antibody deficiency
Raised total protein, narrow band on electrophoresis	Paraprotein - myeloma or MGUS
Ferritin 45,000, fever, cytopenias and splenomegaly	Haemophagocytic lymphohistiocytosis
Positive peanut skin test, eats peanuts without symptoms	Sensitisation - not allergy
Itchy eczema at the site of a watch buckle; positive patch test	Type IV hypersensitivity - nickel
Fever, rash and arthralgia 10 days after antivenom	Serum sickness (type III)
Flushing during a fast vancomycin infusion	Vancomycin infusion reaction (non-IgE) - slow the rate

Exam-style Scenarios

1. A 32-year-old woman has had four pneumonias in 2 years and chronic sinusitis. CT shows bronchiectasis.
Answer: Suspected antibody deficiency.

• Immunoglobulins (IgG, IgA, IgM), protein electrophoresis, FBC, HIV test, specific antibody responses (pneumococcal, tetanus, Hib).
• Exclude secondary causes - drugs, lymphoproliferative disease, protein loss (albumin, urine protein).
• Refer to clinical immunology - CVID is likely if IgG is low with poor vaccine responses; immunoglobulin replacement.

2. A 25-year-old man has meningococcal meningitis caused by serogroup Y. He had meningococcal septicaemia at 17.
Answer: Possible inherited complement deficiency.

• CH50 and AP50 (functional complement) - then individual components (C5–C9, properdin).
• If deficient - meningococcal vaccines (MenACWY and MenB), consider prophylactic antibiotics, emergency antibiotic plan, alert card.
• Screen siblings.

3. A patient with rheumatoid arthritis on tocilizumab has fever and confusion. CRP is 6 mg/L.
Answer: Possible sepsis masked by IL-6 blockade.

• Don't be reassured by a normal CRP - tocilizumab suppresses CRP and fever.
• Sepsis assessment - NEWS2, lactate, cultures, imaging; treat on clinical grounds.
• Hold tocilizumab; also consider GI perforation (a recognised risk).

4. A 40-year-old woman has recurrent facial and hand swelling without hives, and episodes of severe abdominal pain. Antihistamines don't help.
Answer: Suspected hereditary angioedema (bradykinin-mediated).

• C4 (low), then C1 inhibitor level and function.
• Refer to immunology - C1 inhibitor concentrate or icatibant for attacks; prophylaxis.
• Avoid ACE inhibitors and oestrogens; test relatives (autosomal dominant).

5. A 55-year-old man has recurrent chest infections. Total protein is high and albumin low. Immunoglobulins show a high IgG with suppressed IgA and IgM.
Answer: Possible myeloma with immunoparesis.

• Serum protein electrophoresis and immunofixation, serum free light chains, urine Bence Jones protein.
• Calcium, renal function, FBC, bone imaging (whole-body MRI or low-dose CT).
• Haematology referral; infection prevention (vaccines, prophylactic antibiotics).

Key Points

• The infection pattern points to the defect - antibody (sinopulmonary), T cell (viral, fungal, PCP), neutrophil (abscesses, fungi), complement (Neisseria).
• IgG crosses the placenta; IgM is the first antibody; IgA protects mucosa; IgE drives allergy.
• Complement - classical, lectin and alternative pathways converge on C3; C5–C9 forms the membrane attack complex.
• Low C3 and C4 - active SLE; low C4 - HAE; low C3 - post-strep GN and C3 glomerulopathy.
• Gell and Coombs - I IgE, II cytotoxic antibody, III immune complex, IV T cell.
• First-line immunodeficiency tests - FBC, immunoglobulins, electrophoresis, HIV test, vaccine responses.
• Secondary antibody deficiency (rituximab, CLL, myeloma, protein loss) is far commoner than primary.
• IL-6 blockers suppress CRP - don't be falsely reassured.
• Sensitisation (positive test) is not allergy - interpret with the history.
• Avoid unvalidated allergy tests (IgG food tests, vega).

Guidelines and Further Reading

• British Society for Immunology: Clinical immunology resources and immunology for clinicians
• Royal College of Pathologists / UK NEQAS: Immunology test interpretation guidance
• European Society for Immunodeficiencies (ESID): Warning signs and diagnostic criteria
• British Society for Allergy and Clinical Immunology (BSACI): Allergy testing guidance
• NICE CG116: Food allergy in under 19s - assessment and diagnosis
• BNF - for current doses