Lymphatic & Immune System

Fluid is pushed out of blood capillaries by capillary hydrostatic pressure and drawn back mainly by plasma colloid osmotic (oncotic) pressure. In the classic textbook balance, ≈ 20 L/day is filtered and ≈ 17 L reabsorbed, leaving ≈ 3 L/day plus ≈ a quarter to a half of the circulating plasma protein to be returned by lymphatics. (The revised Starling principle holds that most capillaries filter along their whole length and that lymph, partly concentrated in lymph nodes, is the main return route — but the clinically important point is unchanged: without lymph flow, protein accumulates in the interstitium and oedema follows.)

Anything that raises capillary pressure, lowers plasma protein, increases capillary permeability or raises interstitial protein increases lymph formation. Because lymph flow can rise roughly 20-fold as interstitial pressure rises towards 0 mmHg, the lymphatics act as a major safety factor against oedema.

Interstitial fluid enters lymphatic capillaries through overlapping, flap-like endothelial junctions (primary valves) that open when anchoring filaments are pulled taut by rising tissue pressure and close when lymph pressure exceeds tissue pressure. In collecting vessels, flow depends on (1) the intrinsic lymphatic pump — each lymphangion's smooth muscle contracts several times a minute when stretched; (2) extrinsic pumps — skeletal-muscle contraction, arterial pulsation, gut peristalsis and the respiratory pump (falling intrathoracic and rising abdominal pressure during inspiration draws lymph up the thoracic duct); and (3) bicuspid valves that make all of this one-way. Immobility, paralysis and valve damage therefore promote lymphoedema; elevation, exercise and external compression help.

Naive lymphocytes continuously recirculate: blood → high endothelial venules (HEVs) in lymph-node paracortex (or splenic marginal zone, Peyer patches) → lymphoid tissue → efferent lymph → thoracic duct → blood, typically spending hours to about a day in each node before moving on. Entry uses a multistep cascade: L-selectin (CD62L) tethering to peripheral node addressin, chemokine (CCL19/CCL21) signalling via CCR7, and integrin (LFA-1–ICAM-1) arrest before diapedesis. Exit is guided by sphingosine-1-phosphate (S1P) gradients (blocked by the MS drug fingolimod). This patrolling makes it possible for the ≈ 1 in 10⁵–10⁶ lymphocytes specific for a given antigen to find it.

T cells only see peptide fragments bound to MHC molecules. Extracellular (exogenous) antigens are endocytosed, degraded in endolysosomes and loaded onto MHC class II for CD4 helper T cells; cytosolic (endogenous) proteins, such as viral proteins, are cut by the proteasome, pumped into the ER by TAP and loaded onto MHC class I for CD8 cytotoxic T cells. Dendritic cells can also cross-present exogenous antigen on MHC I.

Activation of a naive T cell needs signal 1 (TCR binding peptide–MHC), signal 2 (co-stimulation, chiefly CD28 on the T cell binding B7 — CD80/CD86 — on the antigen-presenting cell) and signal 3 (polarising cytokines). Signal 1 without signal 2 causes anergy, a key mechanism of peripheral tolerance. CTLA-4 and PD-1 are inhibitory checkpoints — the targets of checkpoint-inhibitor cancer drugs.

Each lymphocyte is generated with a single antigen specificity before it ever meets antigen (V(D)J recombination by RAG1/RAG2, plus junctional diversity from TdT). Antigen selects the matching clones, which proliferate (clonal expansion) and differentiate into effector and memory cells (Burnet's clonal selection theory). In T-dependent B-cell responses, activated B cells and follicular helper T cells form germinal centres in lymphoid follicles, where AID-driven somatic hypermutation plus selection on follicular dendritic cells produces affinity maturation, and class-switch recombination changes the antibody from IgM to IgG, IgA or IgE. After the infection clears, ≈ 90–95% of effector cells die by apoptosis (contraction), leaving memory cells.

On first exposure (primary response) there is a lag of about 4–7 days before antibody appears; the response peaks after ≈ 1–2 weeks, is dominated initially by IgM, and is of modest titre and affinity. On re-exposure (secondary/anamnestic response), memory B and T cells respond within ≈ 1–3 days, producing far more antibody (often 10–100-fold or higher), mainly IgG (or IgA/IgE), of higher affinity and longer duration. This is why a second vaccine dose or booster is so effective and why most people get measles or chickenpox only once.

Central tolerance: in the thymus, thymocytes whose receptors cannot recognise self-MHC die (positive selection, cortex), and those that bind self-peptide–MHC too strongly are deleted or diverted to regulatory T cells (negative selection, medulla, helped by the transcription factor AIRE, which drives expression of tissue-restricted self-antigens). Immature B cells that bind self-antigen in the bone marrow undergo receptor editing or deletion. Peripheral tolerance catches escapees: anergy (no co-stimulation), suppression by FOXP3⁺ regulatory T cells, activation-induced death via Fas–FasL, inhibitory receptors (CTLA-4, PD-1) and immune-privileged sites. Failure of tolerance causes autoimmune disease (e.g. AIRE mutation → APS-1; FOXP3 mutation → IPEX; Fas mutation → autoimmune lymphoproliferative syndrome).

A typical bacterial skin infection illustrates the integration: barrier breach → resident macrophages and mast cells sense PAMPs/DAMPs → cytokines (IL-1, TNF-α, IL-6, CXCL8) and complement fragments (C3a, C5a) cause acute inflammation and neutrophil influx → complement C3b and early IgM opsonise microbes → dendritic cells carry antigen in afferent lymph to the draining node → CD4 T cells and B cells are activated (days 4–7) → high-affinity IgG and effector T cells arrive in the tissue and clear the infection → memory remains. Fever and the acute-phase response (CRP, fibrinogen) are systemic expressions of the same cytokines.

Accumulation of protein-rich interstitial fluid due to impaired lymph drainage. Primary forms result from developmental lymphatic defects (e.g. Milroy disease — congenital, FLT4/VEGFR-3 mutation; lymphoedema praecox/Meige disease at puberty). Secondary lymphoedema is far commoner: worldwide the leading cause is lymphatic filariasis (Wuchereria bancrofti, Brugia spp., spread by mosquitoes → elephantiasis); in high-income countries it follows cancer treatment — axillary node dissection and/or radiotherapy for breast cancer (arm lymphoedema in roughly a fifth of patients after axillary clearance, much less after sentinel node biopsy alone), pelvic or inguinal surgery. Early oedema pits; chronic lymphoedema becomes firm and non-pitting with skin thickening, fibrosis, peau d'orange and a positive Stemmer sign (cannot pinch the skin fold at the base of the second toe), and predisposes to recurrent cellulitis and, rarely, lymphangiosarcoma (Stewart–Treves syndrome). Management: complete decongestive therapy (manual lymphatic drainage, multilayer bandaging, compression garments, skin care, exercise) and selected surgery.

Enlarged nodes (generally > 1 cm; > 1.5 cm in the groin) may be localised or generalised. Reactive nodes (infection, inflammation) are typically tender, soft or rubbery, mobile and recent; malignant nodes (metastases, lymphoma) are typically painless, hard (metastatic carcinoma) or rubbery (lymphoma), matted or fixed, > 2 cm, progressive, or supraclavicular — any palpable supraclavicular node is abnormal. A left supraclavicular node (Virchow node, Troisier sign) suggests abdominal malignancy, classically gastric carcinoma, via the thoracic duct. Causes can be remembered as MIAMI: Malignancy, Infection (EBV, CMV, HIV, TB, toxoplasmosis, cat-scratch disease), Autoimmune (SLE, RA), Miscellaneous (sarcoidosis, Kawasaki disease) and Iatrogenic (phenytoin, serum sickness).

Malignant clonal proliferations of lymphocytes, usually presenting as painless lymphadenopathy, sometimes with B symptoms (fever > 38 °C, drenching night sweats, > 10% weight loss in 6 months). Hodgkin lymphoma (≈ 10–15% of lymphomas): bimodal age peaks (young adults and > 55 years), EBV association in some cases, Reed–Sternberg cells (large binucleate "owl-eye" B-derived cells, CD15⁺ CD30⁺) in a reactive background, orderly contiguous spread along node chains (cervical and mediastinal nodes common), alcohol-induced node pain and pruritus; nodular sclerosis is the commonest subtype; generally excellent prognosis. Non-Hodgkin lymphomas (≈ 85–90%): mostly B-cell (diffuse large B-cell lymphoma is the commonest; follicular lymphoma with t(14;18) BCL2; Burkitt with t(8;14) MYC and a "starry-sky" pattern; mantle cell with t(11;14) cyclin D1; gastric MALT lymphoma linked to Helicobacter pylori), older patients, non-contiguous and frequent extranodal spread. Staged by the Ann Arbor/Lugano system.

Clonal malignancies of haematopoietic cells that fill the marrow and spill into the blood, causing marrow failure (anaemia, neutropenic infection, thrombocytopenic bleeding). ALL — commonest childhood cancer (peak 2–5 years), TdT⁺ lymphoblasts, often curable. AML — mainly older adults; myeloblasts with Auer rods; acute promyelocytic leukaemia t(15;17) PML–RARA causes DIC and responds to all-trans retinoic acid. CLL — commonest leukaemia of older adults in Western countries; mature CD5⁺ CD23⁺ B cells, smudge cells, often found incidentally. CML — Philadelphia chromosome t(9;22) BCR–ABL1 tyrosine kinase, massive splenomegaly; its outlook has been transformed by tyrosine-kinase inhibitors such as imatinib. Age mnemonic: ALL CeLLmates have CoMmon AMbitions — ALL children, CLL > 60, CML middle age, AML older adults.

Splenomegaly (> 13 cm) results from congestion (portal hypertension), haematological disease (haemolysis, myeloproliferative neoplasms, lymphoma, leukaemia), infection (EBV, malaria, visceral leishmaniasis, endocarditis), inflammation and storage disease (Gaucher). Massive splenomegaly suggests CML, myelofibrosis, malaria, visceral leishmaniasis or Gaucher disease. An enlarged spleen enlarges towards the right iliac fossa, has a palpable notch, moves with respiration and you cannot get above it. Hypersplenism causes cytopenias. The spleen is the organ most often injured in blunt abdominal trauma (and rib 9–11 fractures); rupture causes haemorrhagic shock and referred left-shoulder-tip pain (Kehr sign, diaphragmatic irritation via the phrenic nerve C3–C5). An enlarged spleen in infectious mononucleosis ruptures easily — avoid contact sports for at least 3–4 weeks. Asplenia (splenectomy, sickle-cell autosplenectomy) predisposes to overwhelming post-splenectomy infection by encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae type b, Neisseria meningitidis); blood films show Howell–Jolly bodies and target cells. Patients need vaccination (ideally ≥ 2 weeks before elective splenectomy), antibiotic prophylaxis and emergency antibiotics.

HIV-1 is a retrovirus whose envelope glycoprotein gp120 binds CD4 plus a chemokine co-receptor (CCR5 in early, macrophage-tropic infection; CXCR4 later). It infects CD4 T cells, macrophages and dendritic cells, integrates its DNA into the host genome, and progressively depletes CD4 T cells, especially in gut-associated lymphoid tissue. Acute seroconversion illness (fever, rash, pharyngitis, lymphadenopathy) is followed by a long clinical latency with persistent generalised lymphadenopathy. AIDS is defined by a CD4 count < 200 cells/µL or an AIDS-defining illness: Pneumocystis jirovecii pneumonia (CD4 < 200), toxoplasmosis and cryptococcal meningitis (< 100), CMV retinitis and Mycobacterium avium complex (< 50), Kaposi sarcoma (HHV-8), primary CNS lymphoma (EBV). Homozygous CCR5-Δ32 deletion confers resistance. Combination antiretroviral therapy restores immunity, and an undetectable viral load means the virus is not sexually transmitted (U = U).

DiGeorge syndrome (22q11.2 deletion): failure of the 3rd and 4th pharyngeal pouches → thymic hypoplasia (T-cell deficiency, absent thymic shadow), hypoparathyroidism (neonatal hypocalcaemic tetany), conotruncal heart defects (tetralogy of Fallot, truncus arteriosus, interrupted aortic arch) and facial anomalies — CATCH-22. Severe combined immunodeficiency (SCID): absent T-cell (and functional B-cell) immunity — commonest is X-linked common γ-chain (IL2RG) deficiency; also adenosine deaminase deficiency and RAG1/2 defects; presents in infancy with failure to thrive, chronic diarrhoea, thrush and opportunistic infections; live vaccines are contraindicated; treated by haematopoietic stem-cell transplantation or gene therapy; detected on newborn screening (low TRECs). X-linked (Bruton) agammaglobulinaemia (BTK): no mature B cells → recurrent bacterial infections after maternal IgG wanes at ≈ 6 months. Selective IgA deficiency is the commonest primary immunodeficiency (≈ 1 in 500 in white populations) — often asymptomatic; anaphylaxis risk with IgA-containing blood products. Chronic granulomatous disease: NADPH-oxidase defect → catalase-positive infections.

A severe, rapid, systemic type I hypersensitivity reaction: allergen cross-links IgE on mast cells and basophils, releasing histamine, tryptase, leukotrienes, prostaglandins and PAF. Within minutes there is airway compromise (laryngeal oedema, stridor, bronchospasm, wheeze), circulatory collapse (vasodilatation and capillary leak → hypotension, tachycardia) and usually skin/mucosal changes (urticaria, angioedema). Common triggers: foods (peanut, tree nuts, shellfish), drugs (β-lactams, NSAIDs, neuromuscular blockers), insect venom and latex. First-line treatment is intramuscular adrenaline (adult 0.5 mg = 0.5 mL of 1 mg/mL into the anterolateral thigh, repeated after 5 minutes if needed), with airway support, high-flow oxygen, lying flat with legs raised and IV fluids; antihistamines and steroids are adjuncts only. Serial mast-cell tryptase confirms the diagnosis; patients receive adrenaline auto-injectors and allergy referral.

Loss of self-tolerance producing tissue damage by autoantibodies (type II/III hypersensitivity) or autoreactive T cells (type IV). Organ-specific examples: type 1 diabetes (T-cell destruction of β cells; anti-GAD), Graves disease (stimulating anti-TSH-receptor antibodies), Hashimoto thyroiditis (anti-TPO), myasthenia gravis (anti-acetylcholine-receptor; associated with thymoma/thymic hyperplasia), pernicious anaemia (anti-intrinsic factor/parietal cell), multiple sclerosis, coeliac disease (HLA-DQ2/DQ8, anti-tissue transglutaminase). Systemic examples: SLE (antinuclear and anti-dsDNA antibodies, immune complexes, low C3/C4), rheumatoid arthritis (HLA-DR4, rheumatoid factor, anti-CCP). Most are commoner in women and are linked to HLA genes (e.g. HLA-B27 with ankylosing spondylitis and reactive arthritis), environmental triggers and molecular mimicry (e.g. rheumatic fever after group A streptococcal infection).

Hyperacute rejection (minutes–hours): preformed recipient antibodies against donor ABO or HLA antigens fix complement on graft endothelium → thrombosis (type II hypersensitivity); prevented by cross-matching. Acute rejection (days to months): T-cell-mediated (CD8 cytotoxicity and CD4-driven inflammation) and/or antibody-mediated; reversible with immunosuppression (calcineurin inhibitors such as tacrolimus/ciclosporin, antiproliferatives, corticosteroids). Chronic rejection (months–years): progressive intimal thickening and fibrosis (e.g. chronic allograft vasculopathy, bronchiolitis obliterans); largely irreversible. In graft-versus-host disease, immunocompetent donor T cells (after haematopoietic stem-cell transplant or, rarely, non-irradiated blood) attack host skin, liver and gut. HLA matching, particularly at HLA-A, -B and -DR, improves graft survival.