The Vasculitides

© Dirk Biddle

1.7.15 Types of Immune Response

As mentioned above, particular vasculitides may elicit differing types of immune response. Commonly termed hypersensitivity reactions, there are four main types (the first three being part of the adaptive humoral system and the fourth being part of the cell-mediated innate system):

Type I is an allergic (or immediate hypersensitivity) reaction, usually IgE-mediated. The antigens in type I reactions may be foodstuff, pollens, drugs, dust, feathers, insect bites or penicillin. Upon first exposure to the antigen, IL-4 will drive B-cells to produce IgE. IgE antibodies then bind to mast cells and basophils. On second exposure the antigen binds to IgE on mast cells and basophils resulting in the release of mast cell and basophil cytoplasmic granules (eg; histamine, serotonin, and bradykinin), as well as the synthesis and secretion of biologically active products of arachidonic acid (eg; leucotrienes). Neutrophils and eosinophils are attracted and mononuclear cells (lymphocytes and monocytes) can also be seen (304). Mast cell products increase vascular permeability and constrict bronchial smooth muscle. A wheal and flare reaction occurs within seconds to minutes. The clinical manifestations of Type I reactions are: Urticaria, angioedema, anaphylactic shock, bronchial asthma and allergic rhinitis.

Type II is an antibody-dependent cytotoxic (or necrotising) reaction caused by either IgM or IgG complement binding antibodies. The antigen in Type II allergic reactions are haptens, which deposit on the cell wall or cell membrane. Type II reactions occur when the antibody binds to either self antigen or foreign antigen on cells, and leads to phagocytosis, natural killer cell activity or complement-mediated lysis. The clinical manifestations of the cytotoxic reactions are: Thrombocytopenia, hemolytic anemia, agranulocytosis and autoimmune diseases.

The main distinction between type II and type III hypersensitivity reaction (see below) is that type II reactions involve antibodies directed to antigens on the surface of specific cells or tissues, whereas type III reactions involve antibodies against widely distributed soluble antigens in the serum. Thus, damage caused by type II reactions is localized to a particular tissue or cell type, whereas damage caused by type III reactions affects those organs where antigen-antibody (immune) complexes are deposited (304). Further, although complement often is required for type II cell injury, and may be detected on the cell or in the tissue, total serum haemolytic complement activity is not depressed, as often occurs in type III immune reactions (x).

Type III is an immune complex reaction. The antigens in this type may be drugs, foreign serum and other different antigens such as from streptococci and tumours. The combination of IgM or IgG antibodies with antigen activates the complement cascade, generating active chemotactic peptides such as C5a, which, in addition to dilating capillaries and increasing vascular permeability, contracts smooth muscle and mobilizes phagocytic cells. Binding of immune complexes to neutrophils and macrophages also activates the respiratory burst with the subsequent generation of toxic oxygen products such as hydrogen peroxide, hydroxyl radical, hypochlorous acid, and chloramines. Lysosomal proteolytic enzymes, together with toxic oxygen products, produce a potent system that can damage protein and lead to blood vessel damage with haemorrhagic necrosis and local tissue destruction (304).

Type IV is a cell-mediated (or delayed hypersensitivity) immune reaction caused by antigen sensitised T-cells. The antigens are different types of chemicals and other substances. Repeated contact of a specific antigen with previously sensitized T-cells leads to stimulation and the release of lymphokines. Lymphokines induce inflammatory reactions and activate macrophages to release mediators. A type IV reaction can be suspected when an inflammatory reaction is characterized histologically by perivascular lymphocytes and macrophages (situated around the vessel) and is most seriously manifested when antigens are trapped in a macrophage and cannot be cleared.

While Type I reactions occur within seconds and minutes following antigen exposure, and immune complex reactions (type III) occur within several hours to one day, type IV reactions can take up to 72 hours to appear. Granulomatous reactions are also important Type IV reactions and develop over a period of weeks.

Type II hypersensitivity reaction may be involved in Microscopic polyangiitis while systemic examples of type III hypersensitivity reactions include Cryoglobulinemia, Henoch-Schönlein purpura, Polyarteritis nodosa, Systemic lupus erythematosus, Rheumatoid arthritis, and most glomerulonephritis. Vasculitis conditions presenting with cell-mediated type IV hypersensitivity reaction include CNS vasculitis and Wegener’s granulomatosis.

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Hypersensitivity: A state of altered reactivity in which the body reacts with an exaggerated immune response to a foreign substance.
Hypersensitivity reactions are classified as immediate or delayed, types I and IV, respectively, in the Gell and Coombs classification of immune responses. (OMD),
Cytoplasm: The organized complex of inorganic and organic substances external to the nuclear membrane of a cell and including the cytosol and membrane-bound organelles (such as mitochondria , lysosomes , ribosomes ). (OMD)",
ArachidonicA liquid unsaturated fatty acid C20H32O2 that occurs in most animal fats, is a precursor of prostaglandins , and is considered essential in animal nutrition. (M+),
Leucotriene: A family of hydroxyeicosotrienenoic (HETE) acid derivatives in which the lipid moiety is conjugated to glutathione or cysteine and that are generated in basophils, mast cells, macrophages and human lung tissue by lipoxygenase-catalyzed oxygenation.
- especially of arachidonic acid and that participate in allergic responses (as bronchoconstriction in asthma) -- see slow reacting substance of anaphylaxis.
Members of the group are potent pharmacological mediators, for example SRS A, the slow reacting substance of anaphylaxis - a mixture of three leukotrienes produced in anaphylaxis that causes contraction of smooth muscle after minutes in contrast to histamine which acts in seconds and that is probably responsible for the bronchoconstriction occurring in anaphylaxis.,
MononuclearHaving only one nucleus,
Cytotoxic: (cell poison) Chemicals that are directly toxic to cells, preventing their reproduction or growth. Cytotoxic agents can, as a side effect, damage healthy, non-cancerous tissues or organs which have a high proportion of actively dividing cells, for example, bone marrow, hair follicles. These side effects limit the amount and frequency of drug administration. (OMD),
Complement: (C? ) A term originally used to refer to the heat labile factor in serum that causes immune cytolysis , the lysis of antibody coated cells and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed components of complement and are designated by the symbols C1 through C9. C1 is a calcium dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower case letter suffixes, for example, C3a. Inactivated fragments may be designated with the suffix i, for example C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol for example C1 or C4b, 2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3, C1q binds to a single IgM molecule or two adjacent IgG molecules.
The alternative pathway can be activated by IgA immune complexes and also by non-immunologic materials including bacterial endotoxins , microbial polysaccharides and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3, activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins , opsonins or chemotactic factors. (OMD),
Haptens: Small antigenic determinants capable of eliciting an immune response only when coupled to a carrier. Haptens bind to antibodies but by themselves cannot elicit an antibody response. (OMD)
A small separable part of an antigen that reacts specifically with an antibody but is incapable of stimulating antibody production except in combination with an associated protein molecule. (M+),
Haemolysis: Lysis of red blood cells with liberation of haemoglobin.(M+),
Immune Complexes: Multimolecular antibody antigen complexes that may be soluble or insoluble depending upon their size and whether or not complement is present . Immune complexes can be filtered from plasma in the kidney and the deposition of the complexes gives rise to glomerulonephritis probably because of the trapping of neutrophils via their Fc receptors. (OMD),
Respiratory Burst: Response of phagocytes to particles (particularly if opsonised) and to agonists such as formyl peptides and phorbol esters, an enhanced uptake of oxygen leads to the production, by an NADH dependent system, of hydrogen peroxide, superoxide anions and hydroxyl radicals, all of which play a part in bactericidal activity. (OMD),
Hydrogen Peroxide: An unstable compound (H2O2) used especially as an oxidizing and bleaching agent and as an antiseptic. (M+)
Hydrogen peroxide is produced by vertebrate phagocytes and is used in bacterial killing (the myeloperoxidase halide system). (OMD),
Hydroxyl Radicals: Hydroxyl. The univalent radical OH. This radical is characteristic of hydroxides, oxygen acids, alcohols, glycols, phenols, and hemiacetals. (OMD),
Hypochlorus Acid: An oxyacid of chlorine containing monovalent chlorine that acts as an oxidizing or reducing agent.
It is derived from chlorine, not known in a pure state, but forming various salts, called hypochlorites. (OMD)
An unstable strongly oxidizing but weak acid (HCLO) obtained in solution along with hydrochloric acid by reaction of chlorine with water and used especially in the form of salts as an oxidizing agent, bleaching agent, disinfectant, and chlorinating agent. (M+),
Chloramines: Chloramine B: Sodium N-chlorobenzenesulfonamide;a nontoxic antiseptic substance used in wound irrigation as a substitute for chloramine T.
Chloramine T: Sodium N-chloro-p-toluenesulfonamide;a nontoxic but strong antiseptic used in the irrigation of wounds and infected cavities. (OMD),
Cell-Mediated Immunity: Immune response that involves effector T-lymphocytes and not the production of humoral antibody.
Responsible for allograft rejection, delayed hypersensitivity and in defence against viral infection and intracellular protozoan parasites. (OMD),
Perivascular: Situated around a vessel