Inflammation and Immunity

Innate immunity includes mechanical barriers (epithelium), inflammation (leading to phagocytosis by neutrophils and macrophages), anti-viral defense (dendritic cells and natrural killer NK cells), complement system. Adaptive immunity inovolves lymphocytes and antibodies; includes humoral (against extracellular microbes/toxins) and cell-mediated (against intraceuular microbes) immunity.

Cells of the Immune System

Cells include:

  • Neutrophils (polymorphonuclear PMN cells) – From precursor cells in bone marrow. Most numerous white cell in blood, increasing in number in acute inflammation. Short life span once activated in tissues. Motile (amoeboid) and able to move from vessels into tissues, movement can be directional, attracted by chemotaxins. Actively phagocytic, contain granules rich in a variety of proteases with generated free radicals killing phagocytosed bacteria. Produce arachidonic acid to facilitate prostaglandin production. Increased neutrophil production by bone marrow is caused by cytokines.
  • Reticuloendothelial system (mononuclear phogocytes system) – Includes blood monocytes and tissue macrophages in the liver (Kupffer cells), spleen, LN (sinus histiocytes), lungs (alveolar macrophages) and CNS (microglia).
    • Monocytes – Half-life ~1day in blood) arise from bone marrow precursors, differentiate into macrophages in tissues (half life months-years).
    • Macrophages – Help eliminate microbes and initiate repair, but also cause tissue injury in chronic inflammation. Once they phagocytose microbes, peptide fragment antigens are presented to T cells, acting as APCs.
  • Lymphocytes – Antigen-stimulated lymphocytes interact bidirectionally with macrophages, increasing the severity and chronicity of the reaction (immune inflammation). Naive mature lymphocytes have not encouted antigen for which they are specific, become effector cells when they are activated by antigen. Some convert to memory cells which are in a state of heightened awareness, increasing rapidity of response on re-infection. In strong chronic reations lymphocytes accumulate with antigen-presenting cells (APCs) and plasma cells to form tertiary lymphoid organs (similar to lymph nodes).
    • T Lymphocytes – Develop from precursors in the thymus, consisting of 60-70% of circulating lymphocytes. Each recognise a specific antigen by antigen-specific T-cell receptor (TCR) linked to the CD3 complex (TCR complex) CD4/helper cells function secrete cytokines to help macrophages and B lymphocytes. CD8/cytotoxic/CTL/killer cells cells destroy host cells harboring microbes. They are activated by binding to antigen-MHC (major histocompatibility complex) complexes on the infected antigen presenting cell (APC). Suppressor T cells supress production of antibodies.
    • B Lymphocytes – Develop from precursors in the bone marrow, consisting of 10-20% of circulating lymphocytes, but also present in peripheral lymphoid tissues (lymph nodes, spleen, mucosa-associated lymphoid tissues MALT). Specific membrane bound antibodies (IgM, IgD), when bound to antigen cause conversion into plasma cells that secrete antibodies, complement receptors etc.
    • Natural Killer (NK) cells (large granular lymphocytes) – 10-15% of circulating lympohcytes. Don’t express TCRs or Ig, are able to kill infected and tumour cells without prior exposure or activiation. Important early lne of defence against viral infections and some tumours.
  • Dendritic cells – The msot important APCs for initiating T-cell responses. Langerhans cells are immature dendritic cells in the epidermis. They are recruited to the T-cell zones of lymphoid organs.
  • Eosinophils – Abundant in IgE and parasitic mediated reactions. Granules contain major basic protein toxic to parasites, but also cause lysis of normal epithelial cells.
  • Mast cells – Distributed throught connective tissue. Suface has receptors for IgE. Degranuate to release histamine and prostalglandins.

Acute Inflammation

Increase in blood flow; increased permeability (allowing leak of plasma proteins and leukocytes); emigration, accumulation and activation of leukocytes. Exudate is excape of fluids, protein sn ad blood cells into interstitium or body cavity. Transudate is fluid with low protein content. Oedema is excess of interstitial fluid, either exudate or transudate. Pus is purulent exudate rich in leukocytes, debris of dead cells and occasionally microbes.

Triggers include:

  • Infection – Bacteria, viruses, fungi, parasites and their toxins.
  • Tissue necrosis – From ischaemia, truama, physical/chemical injury. Hypoxia causes inflammation and necrosis.
  • Foreign bodies – Usually from traumatic injury or the accompanying microbes.
  • Immune/hypersensitivity reaction.


  • Vascular phase
    • Vasodilatation – From histamine, NO, prostaglandins, complement (C3a and C5a) causing erythema.
    • Increased permeability (vascular leakage) – Contraction of endothelial cells increasing inter-endothelial spaces (histamine, bradykinin, leukotrienes, neuropeptide substance P; rapid and short-lived), endothelial injury causing necrosis and detachment (severe injuries, adherence of neutrophils), transcytosis (increased transport of fluids and porteins trough the cell).
    • Stasis/congestion – Loss of vascular fluid increases blood viscosity and slower flow), adherence of leukocytes along endothelium.
    • New blood and lymphatic vessels.
  • Exudative phase – Fluid and cells escape from vessels. Leukocytes (esp neutrophils, macrophages) are capable of phagocytosis and killing of microbes, elimination of necrotic tissue and foreign substances, release growth factors for repair. They also cause tissue damage and prolong inflammation. Extravasation includes:
    • Margination – Slower flow/stasis causes leukocytes to displace peripherally.
    • Rolling – Transient adherence and detachment to endothelium, initiated by selectins.
    • Adhesion – To the endothelium, mediated by integrins.
    • Transmigration (diapedesis) – Across the endothelium esp post-capillary venules. Piece the basement membrane by secreting collagenases, entering extravascular space. Mediated by complement C5a, leukotrines.
    • Chemotaxis – Locomotion of leukocytes along a chemical gradient (bacterial products, cytokines, complemnt system (esp C5a), arahidonic acide metabolites. Neutrophiles predominante in the 1st 6-24hrs, monocytes after 24-48hrs. Neutrophils are short lived, undergoing apoptosis, whereas monocytes survive longer and may proliferate in tissues. Neutrophils remain the predominant cell in Pseudomonas infeections; lymphocytes in viral infections; eosonophils in some hypersensitivity reactions.
  • Recognition of microbes and activation of leukocytes. Receptors include toll-like receptors (TLRs), G protein-coupled receptors, receptors for opsonins and cytokines.
  • Phagocytosis – Regoctitiona and attachment of the particle, engulfment (phagosome formation), the killing and degredation (reactive oxygen and nigrogen species, enzymes stored in lysosomes). Best perfromed with activated macrophages (differentiated monocytes).
  • Termination of inflammatory response – Mediators of inflammation are produced in rapid bursts, only as long as the stimulus persists and have short half-lives. Neutrophiles only survive a few hours in tissues, dying by apoptosis. Active termination from switch of arachidonic acid from pro-inflammatory leukotrienes to anti-inflammatory lipoxins, anti-inflammatory cytokines and neural impulses (cholinergic discharge).

Mediators of inflammation are cell derived (platelets, neutrophils, monocytes/macrophages, mast cells, occasionally mesenchymal and epithelial cells) or plasma-derived (complement, kinins). Active mediators are produced only in response to microbes and damaged tissue. One mediator can stimulate release of other mediators, and can act on one or many differing cell types. Most are short-lived, or actively scavenged/inhibited.

  • Vasoactive amines cause dilatation of arterioles and permeability of venules.
    • Histamine – Mostly stored in granules within mast cells, in connective tissue adjacent to blood vessels. Mast cell degranulation ocurs from physical injury, antibody binding, complement binding, histamine-releasing proteins from leukocytes, neuropeptides (eg substance P) and cytokines.
    • Serotonin – Mostly platelets and some neuroendocrine cells. Release stimulated after contact with collagen, thrombin, or antigen-antibody complexes. Similar actions as histamine.
  • Arachidonic acid (AA) metabolites:
    • Prostaglandins (PGs) – From mast cells, macrophages, endothelial cells etc. Involved in vascular and systemic (pai, fever) reactions.
    • Leukotrienes – Secreted by leukocytes as chemoattractants, also have vascular effets (more potent than histamine).
    • Lipoxins – Inhibitor of inflammation, inhibiting leukocyte recruitment and cellular components of inflammation.
  • Platelet-activating factor (PAF) – From platelets, basophils, mast cells, neutrophils, macrophages, endothelial cells. Causes platelet aggregation, vasoconstriction (vasodilatation at low concentrations), venular permeability, bronchoconstriction, leukocyte adhesion, chemotaxis, degranulation.
  • Reactive oxygen species (free radicals) – Cause endothelial damage (increasing permeability), damage to other cell types, inactivates antiproteases (eg α1-antitrypsin).
  • Nitric oxide (NO) – From endothelium, maccrophages and some neuornes. Cuases vasodilataiton and inhibits cellular component of inflammation.
  • Cytokines – Include tumour necfosis factor (TNF), interleukins (IL) and chemokines; made by macrophages and others. TNF and IL-1 stimulate endothelial adhesion and secretion of other cytokines. IL-6 induce systemic effects. Chemokines recruit and migrate leukocytes to sites of inflammation.
  • Plasma derived mediators – Complement, coagulation and kinin systems.

Lymphangitis is inflammation of the lymphatics, lymphadenitis of the draining lymph nodes.

Outcomes of acute inflammation:

  • Complete resolution – When injury is limited or short-lived. Little tissue destruction and parenchymal cells can regenerate. Cellular debris and microbes removed by macrophages, oedema resporbed by lymphatics.
  • Fibrosis (organisation) – Substantial tissue destruction, tissue incapable of regeneration, or when there is abundant fibrin exudate. Infiltration of new capillaries, macrophages, fibroblasts, and myofibroblasts. Intervening spaces between the vessels become progressively filled with fibroblasts synthesising collagen.
  • Progression to chronic inflammation – When the acute inflammation cannot be resolved due to persisting agent or infererence with normal healing.

Morphologic patterns:

  • Serous inflammation – Prominent thin fluid (from plasma or secretion of mesothelial cells).
  • Fibrinous inflammation – Large fibrinogen molecules exit through increased vascular permeability, depositing fibrin. Occurs when the vascular leaks are large or local procoagulant stimulus eg cancer. Characteristic of meninges, pericardium, pleura. If fibrin is not cleared, it may stimulate ingrowth of fibroblasts and blood vessels leading to scarring (organisation).
  • Suppurative/purulent inflammation – Large amounts of pus/purulent exudate (neutrophils, liquefacti ve necrosis, oedema fluid), from pyogenic bacteria (eg staph). Abscesses are localised collections of pus, usually surrounded by preserved zone of neutrophiles, vascular dilatation and fibroblastic proliferation.
  • Ulceration – Defect from sloughing/shedding of inflammed necrotic tissue, esp mucosa (mouth, stomach, intestines, GU) or skin/subcutaneous tissues (preixisting ischaemia).

Chronic Inflammation

Prolonged inflammation (weeks-months), following acute inflammation or insidious low-grade reaction (most). Tissue damage, acute inflammation, granulation tissue, repair, and immune response all take place concurrently. Eventually heals by scarring. From persistent infections difficult to eradicate (mycobacteria, some viruses, fungi, parasites; often evoke delayed hypersensitivity and granulomas), immune-mediated (auto-immune, unregulated response against microbes or response againsed an enveironmenatl substance) or prolonged esposure to potentially toxic agents (eg silica, atherosclerosis against endogenous plasma lipid). There is infiltration of mononuclear cells (macrophages, lymphocytes, plasma cells), dissue destruction and attempts at healing (connective tissue replacement – angiogenesis and fibrosis).

Granulomatous inflammation is a pattern of chronic inflammation. Stronge activation of T cells causing macrophage activation. Granulomas are aggregations of macrophages transformed into epetheiliod histiocytes surrounded by mononuclear cells (lymphocytes, occasionally plasma cells) and later fibroblasts and connective tissue. Epithelioid cells fuse to form giant cells. Occurs with mycobacteria (eg TB), some fungi, parasites (larvae, eggs, worms), syphilis, foreign bodies, exogenous materials (talc, silica, sutre, oils, silicone), beryllium, some drugs (allopurinol, sulphonamides), Crohn disease, sarcoidosis, Wegener’s. May be complicated by secondary (reactive) amyloidosis. Tuberculomas (in TB) have central caseous necrosis (rare in other granulomas).

Systemic Effects of Inflammation

(Acute-phase response, systemic inflammatory response syndrome). Initiated by cytokines. Changes include:

  • Fever – Stimulated by pyrogens (IL-1, FNR, gram-negative bacterial endotoxin/lipopolysaccharide/LPS). ?induces heat shock proteins that enhance lymphocyte response.
  • Acute-phase proteins – Include CRP, fibrinogen, serum amyloid A (SAA) produced by the liver. CRP and SAA bind to microbial walls, acting as opsonins. Prolonged production of esp SAA may cause secondary amyloidosis.
  • Leukocytosis – Nutrophilia with bacteria; lymphocytosis with viral infections; eosinophilia in asthma, allergy and parasites.
  • Tachycardia, hypertension, reduced sweating, rigors, chills, anorexia, somnolence, malaise.

Adaptive Immunity

Antigens are any substance capable of inducing an immue response or any substance that react with antibodies or primed T-cells. Lymphocytes are specific to a certain antigen, with ~107-109 different specificites in the total pool of ~1012 adult lymphocytes. The certain antigen causes activation = clonal selection hypothesis.

Cell-mediated immunity (CMI) – Naive T lymphocytes activated by APCs in peripheral lymphoid organs, proliferate and differentiated into effector cells that migrate to sites where the antigen is present. CD4+ helper cells activate the presenting macrophages and B lymphocytes, activate eosinophils and mast cells, recruit neutrophils and monocytes. Activated Cd8+ killer cells that kill cells infected by micropes.

Humoural immunity – Activated B lymphocytes proliferate and differentiate into plasma cells that secrete antibodies with a specific antigen binding site the same as the cell surface antibodies recognising the antigen. Antibodies consist of a variable antigen-binding fragment (Fab) and constant crystallisable (Fc) fragment (determining type of antigen). Polysaccharide and lipid antigens stimulate mainly IgM; protein stimulate IgG, IgA and IgE. IgG coat (opsonize) microbes, targetting them for phagocytosis, as phagocytes (neutrophils and macrophages) express receptors fot the Fc tails. IgT and IgM also activate the complement system that promotse phagocytosis and microbial destruction. IgA from mucasal epithelium neutralises microbes in the lumens of mucosal tractus (respiratory, GIT). IgG is actively transported across the placenta, protecting the newborn. Most circulating IgG have half-lives of ~3 weeks. Some antibody-secreting plsma cells migrate to bone marrow, continuing to produce low levels of antibodies for years.

Most activated lymphocytes die by apoptosis after microbe is eliminated. Initial activation also generates memory cells which are an expanded pool the respond faster and more effectively when antigen is re-exposed (vaccination), which survive for years after infection.

Hypersensitivity Reactions

Severe and harmful immunological reactions, types include:

  • Type I (immediate) hypersensitivity – IgE coats mast cells and basophils (becoming sensitised). Re-exposure to antigens causes degranulation and release of histamine, leukotrienes and prostaglandin. These cause vasodilatation, increased capillary permeability, smooth muscle spasm, leukocyte extravasation. Multisystemic reaction results in anaphylactic shock. Includes atopy, asthma, anaphylaxis.
  • Type II (cytotoxic) hypersensitivity – Antigens (intrinsic/’self’ or extrinsic) bound to cell surfaces recognised by macrophages and dendritic cells (antigen presenting cells, APCs). This induces B cells to produce IgG and IgM, activating classical pathway of complement. Takes hours to days. Includes autoimmune haemolytic anaemia (Rh), haemolytic disease of the newborn, autoimmune thrombocytic purpura (glycogen IIb/IIIa on platelets), pemphigus vulgaris (epidermoid cadherins), ANCA vasculitides (neutrophil granule proteins), Goodpastures syndrome (collagen type IV), acute rheumatic fever (grp A strep them myocardial antigen), pernicious anaemia (intrinsic factor on gastric parietal cells). Antigens against cell surface receptors (‘type V hypersensitivity’) rather than cell surface component, preventing intended ligand binding; includes myasthenia gravis (acetylcholine receptor), Graves disease (TSH receptor)
  • Type III (immune complex) hypersensitivity – Solube antigens not bound to cell surfaces bind to IgG and IgM forming immune complexes of varying sizes. Larger complexes cleared by macrophages, smaller complexes induce inflammation (activate complement) wherever they deposit (small vessels, joints, glomeruli). Takes hours to weeks. Includes SLE (nuclear antigens), post-streptococcal glomerulonephritis, polyarteritis nodosa (Hep B), reactive arthritis (various bacterial antigens), serum sickness, Athus reaction (local reaction eg Farmer’s lung)
  • Type IV (delayed type/cell-mediated) hypersensitivity – Macrophages are APCs presenting antigen to CD4 helper T cells (release activating cytokines for macrophage to kill microbe) and CD8 cytotoxic T cells (kill cell on contact). Takes 2-3 days. Associated with granuloma formation. Includes DM1 (pancreatic beta cells), MS (oligodendrocyte proteins), RA (synovial membrane), some peripheral neuropathies (Schwann cell), Crohn’s disease (unknown antigen), contact dermatitis (eg poison ivy, nickel), Mantoux test (tubercullin), temporal arteritis, Hashimoto thyroiditis, coeliac disease, GVHD, chronic transplant rejection.

Autoimmune Diseases

(Immune-mediated inflammatory diseases). Autoantibodies are found in apparantly normal individuals, esp elderly. Pathologic autoimmunity causes an immune reaction not secoundary to tisue damage or other cause. Arises from combindation of susceptibile genes (may cause breakdown of self-tolerance) and environmental triggers. Certain HLA (human leukocyte antigen) alleles (encoding MHC (major histocompatibility complex) molecules are variably associated with inflammatory diseases, including B27 (ankylosing spondylitis, postgonococal arthritis, acute anterior uvietis), DR4 (RA, type 1 DM), DR3 (chronic active hepatitis, primary Sjogren syndrome, type 1 DM). Infections may up-regulate expression of costimulators of APCs, and some microbes may express antigens with same amino acid sequences as self-antigens (molecular mimicry eg rheumatic heart disease). Once the disease is induced, it tends to be progressive with occasionally relapses and remissions; the immune system has intrinsic amplification loops and inflammation damages tissue releasing further self-antigens.

Acquired Immunodeficiency Syndrome (AIDS)

From the retrovirus human immunodeficiency virus (HIV). Risk factors include homosexual/bisexual men, IVDU, reciepients of blood products esp haemophilia (<1985). Most paediatic patients trnasmitted from mother. Transmission is sexual (>75%), parental or mother-to-infant (10-50% transmission transplacental, intrapartum or via breast milk; eliminated with antiretroviral therapy). After needle-stick accidents secoconversion in 0.3%, reduced by 8x with antiretroviral therapy within 24-46hrs.

HIV infects CD4+ T cells, macrophages, dendritic cells and CNS microglia. The acute retroviral syndrome is a self-limited flu-like illness initiating 3-6 weeks posterior infection and resolving after 2-4 weeks. The virus integrates into the host genome (via reverse RNA transcription synthesising complementary/proviral DNA), then remains latent for months-years. Activation of the T cell (antigens/cytokines) induces viral replication and release of new viruses. Loss of T-cells is due to direct infeciton, destruction of lymphoid organs, loss of precursors. This chronic phase slowly and progressively destrys T cells, early in disease they are replaced almost as quickly as they are destroyed, after years there is steady decline in CD4+ T cell numbers in lymphoid tissues and circulation. Pts are asymptomatic or develop minor opportunistic infectiosn (oral candidiasis, vaginal candidiasis, herpes zoster TB), autoimmune thrombocytopenia. AIDS is the final phase (after 7-10yrs if untreated) with breakdown of host defences, dramatic increase in plasma virus with persisting fever, fatiuqe, weight loss, diarrhoea, generalysed lymphadenopathy, opportunistic infections, secondary neoplasams and neurologic disease. Opportunistic infections include PCP, Candida, CMV, mycobacteria (atypical and typical esp MAI), Cryptococcus neoformans, toxoplasma gondii, Cryptosporidium, HSV, papavavirus (JC virus), Histoplasma capsulatum. Tumours (in 25-40%) include Kaposi sarcoma (from kaposi sarcoma herpesvirus), non-Hodgkin B-cell lymphoma (from EBV), cervical and anal cancer (from HPV).