• an infection in which the host immune response fails to eradicate the organism
• environmental antigen in which there is persistent or frequent exposure
• autoimmunity

Asthma

Asthma is essentially a disease in which the primary physiological manifestation is reversible airflow limitation. Although clinical asthma is subdivided into extrinsic (ie where there is a recognised external trigger) and intrinsic (where the trigger is either non-antigenic or not recognised) forms, it is believed that in all cases the initial development of the condition involves type I hypersensitivity to an inhaled antigen. Nevertheless most individuals with such hypersensitivity do not go on to develop the chronic inflammatory condition which we term asthma, whose definition includes long-term changes such as connective tissue deposition and hypertrophy of the bronchial smooth muscles in addition to inflammatory and immunological criteria.

In cases of extrinsic asthma, the patient is believed to be chronically or periodically exposed to the antigenic stimulus at very low level, which may not always trigger an clear response. This exposure leads to a hyperreactivity of the bronchioles to inflammatory mediators. If you measure the reduction in airway function after experimental intrabronchial challenge with an inflammatory mediator (eg histamine), asthmatics show a characteristically high sensitivity which is related to the severity of their disease.

What is the cause of this hyperreactivity? One clue is that the effect is reversible, so that asthmatics who are rigorously isolated from triggering stimuli gradually lose hyperreactivity over a period of months. This loss correlates with changes in the cell populations found in the lungs. Asthmatics have an increase in mast cell density and a very significant increase in both eosinophils and T cells. The abnormal cell accumulations are believed to be antigen-driven by stimulation of the T_H2 cells found in the lungs of asthmatics. Cytokines produced by T_H2 cells can stimulate eosinophil production, recruitment and activation. In addition a poorly characterised factor has been observed to 'prime' mast cells so as to reduce their threshold for activation.

Rheumatoid arthritis

Although we are extremely ignorant about the causes of this autoimmune disease, and for example the roles played by ' rheumatoid factor ' (IgM anti-IgG antibody) and antibody glycosylation, it is a chronic inflammatory disease which there is an immune response dominated by T_H1 cells, akin to type IV hypersensitive reactions. We know that the inflammation can be temporarily eliminated (almost) either by causing destruction of most of the T cells (by eliciting a type II reaction after infusion of a suitable monoclonal antibody) or by a short course of treatment with anti-TNFalpha monoclonal antibody. This amelioration lasts for a few months.

The implications of this are that the continuous stimulation of T cells is required to maintain the inflammatory process and that TNFalpha plays a key role in that process. The currently accepted view is that whatever initiates the disease, once joint damage is established it is a self-perpetuating process in which auto-antigens released as a result of the damage stimulate T cells which recruit and activate macrophages which lead in turn to further damage, the maintenance of inflammation - via vascular endothelial activation - and the perpetuation of the proliferation and cytokine secretion of local T_H1 cells. Presumptively the key cytokines are TNFalpha and IL-12 released by macrophages and IFNgamma from T cells.

Information provided by: http://www-immuno.path.cam.ac.uk