Pathology caused by the cellmediated immune response

The mere expression of a cell-mediated immune response involves some degree of inflammation, lymphocyte infiltration, macrophage accumulation and activation and can therefore by itself cause pathological changes. This type of response predominates in the pathogenesis of tuberculosis, with mononuclear cell infiltration, degeneration of parasitised macrophages, and the formation of giant cells as central features. In chronic mycobacterial infection, the continuous release of microbial antigens leads to a chronic inflammatory response and the formation of granulomas. This particular pathological feature is also associated with a range of other chronic microbial and parasitic diseases including bacterial (leprosy and syphilis), chlamydial (lymphogranuloma inguinale), and fungal (coccidiomycosis) infections.

Mononuclear cells also cause pathological changes during a cell-mediated response by lysing host cells. When the latter are infected by a virus, antigens are expressed on their surfaces providing a target for cell-mediated responses. In this way, cell-mediated immunity may contribute to the pathology of hepatitis B infection and many herpes and poxvirus infections. In addition, the autoimmune damage associated with Chagas' disease may be due to the adsorption of antigens from Trypanosoma cruzi on uninfected host cells, allowing recognition by Tcyt or destruction by antibody-dependent cellular cytotoxicity.

Chagas' disease is caused by Trypanosoma cruzi and is transmitted by blood-sucking insects. The organisms spread throughout the body during the acute infection. Years later, a poorly understood chronic disease appears, involving the heart and the intestinal tract. These organs contain only small numbers of the parasite but show a loss of autonomic ganglion cells. It is thought the pathology arises as a result of an autoimmune reaction since a monoclonal antibody to T. cruzi has been obtained that cross-reacts with mammalian neurons.

One human virus infection in which a cell-mediated immune response appears to contribute greatly to the pathology of the disease is measles. This is evidenced by the fact that children with thymic aplasia suffer a fatal disease if they are infected with measles virus. Individuals with this particular immunodeficiency generally fail to develop antigen-specific T cell responses and cell-mediated immunity but have normal antibody responses. Thus, instead of the limited virus growth and respiratory disease seen in normal children, those with thymic aplasia show uncontrolled virus replication in the lung (despite specific antibody formation), resulting in giant cell pneumonia. In addition, the typical measles rash is absent. These studies indicate that the cellmediated immune response is essential for regulation of virus growth and for the production of the characteristic skin lesions. Other studies have suggested that a similar conclusion can be drawn about the rashes in poxvirus infection.

Superantigens: The toxins of Staphylococcus aureus and Streptococcus pyogenes belong to a family of exotoxins which have a profound effect on the immune system. These bacterial superantigens promote cell-mediated immunity by stimulating T cell activation and recruitment to local sites of inflammation. The T cell-stimulating activity contributes to the pathogenesis of the respective diseases.

Superantigens stimulate both CD4+ and CD8+ T cells, as well as a fraction of T cells with antigen receptors, which are composed of gamma and delta chains (Tgd). Stimulation is caused by cross-linking variable parts of the T cell antigen receptor and non-polymorphic parts of MHC Class II molecules on antigen presenting cells (Figure 6.8). For T cells with an antigen receptor composed of alpha and beta chains (Taj3), the variable region of the b chain provides the site of attachment for the superantigen.

The T cell activation properties of superantigens have been implicated in a number of diseases where the consequence of this activation is pathogenetic. In allergy, superantigens induce the production of the proinflammatory cytokines interleukin 1 and tumour necrosis factor alpha, which enhance the expression of E-selectin. One ligand for E-selectin is cutaneous lymphocyte-associated antigen (CLA), which is found on T cells invading the skin in allergic individuals; its expression being induced by IL-12 presumably released by Langerhans cells or other antigen presenting cells upon stimulation with superantigen. Evidence

Figure 6.8 Superantigen stimulation of Tcells

Unlike processed antigen presented to T cells, superantigens are able to bind to the relatively constant regions of the MHC and TCR, outside the normal antigen-presenting/binding regions. This brings the cells into close aposition, allowing the interaction of co-stimulatory molecules. This means that superantigens lead to polyclonal activation of Tcells that does not depend upon their antigen specificity.

Figure 6.8 Superantigen stimulation of Tcells

Unlike processed antigen presented to T cells, superantigens are able to bind to the relatively constant regions of the MHC and TCR, outside the normal antigen-presenting/binding regions. This brings the cells into close aposition, allowing the interaction of co-stimulatory molecules. This means that superantigens lead to polyclonal activation of Tcells that does not depend upon their antigen specificity.

Table 6.6 Evidence of a role for superantigen in atopic dermatitis

Evidence:

Staphylococcus aureus isolated from skin lesions of patients with atopic dermatitis secrete large amounts of superantigen whilst those isolated from non-atopic (allergic) individuals do not

Skin colonisation by Staph. aureus can cause severe exacerbation of atopic dermatitis

Anti-Staph. aureus superantigen IgE has been found in patients undergoing exacerbation of atopic dermatitis due to Staph. aureus colonisation

Peripheral blood basophils'armed'with anti-Staph. aureus superantigen IgE undergo degranulation and release histamine upon challenge in vitro with superantigen that superantigens also influence antibody-mediated allergic responses is largely anecdotal but quite convincing (Table 6.6).

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