Chapter 24 John Isaacs1 and Nishanthi Thalayasingam2 1 Newcastle University and Newcastle upon Tyne Hospitals NHS Trust, Newcastle, UK 2 Institute of Cellular Medicine, Newcastle University, Newcastle, UK The classic hallmarks of inflammation: calor (heat), dolor (pain), rubor (redness) and tumor (swelling), occur at sites of tissue damage. These changes are a consequence of blood vessel dilatation, increased capillary permeability, recruitment of innate immune cells such as polymorphonuclear leucocytes and monocytes from the bloodstream and subsequent release of proinflammatory mediators (Figure 24.1). The innate immune cells become activated and are important for phagocytosis of pathogens and subsequently for tissue repair. Antigen‐presenting cells (APCs) in the inflamed tissue also become activated, by ‘danger signals’ released by pathogens or by tissue damage itself. APCs include dendritic cells and macrophages, and act as the bridge between the two arms of the immune response. In health, this leads to an immune response against pathogens but in autoimmunity these processes become subverted and autoreactive lymphocytes are triggered, leading to an unregulated immune response against self. The mediators released (cytokines, chemokines, growth factors) lead to further immune cell influx, new blood vessel formation plus the activation of resident tissue cells, resulting in further tissue damage (Figure 24.2). APCs internalize and digest (process) the pathogen, then migrate to local lymph nodes where they initiate an immune response by ‘presenting’ the processed antigen to lymphocytes. Lymphocytes (B‐cells and T‐cells) express specialized receptors on their surface which recognize antigen. T‐cells respond to antigenic fragments displayed on the surface of APCs, in association with major histocompatibility complex (MHC) molecules, whereas B‐cells interact with intact antigens. Following antigen recognition, lymphocytes proliferate and differentiate into effector cells: cytotoxic and helper T‐cells, and memory B‐cells and plasma cells. A proportion remain in the lymphoid tissue but the remainder enter the circulation and migrate to areas of inflammation. T‐cells develop in the thymus. Helper T‐cells express the CD4 co‐receptor and are central to the co‐ordination of immune responses. This involves cytokine release but they also provide help for B‐cell maturation and antibody production via molecules such as CD40 ligand (CD40L). Three factors are required for T‐cell expansion and differentiation: recognition of the antigen by its specific lymphocyte receptor (signal 1), binding of co‐stimulatory molecules (signal 2) and receipt of appropriate cytokine signals (signal 3) (Figure 24.3). CD80 and CD86 are key co‐stimulatory molecules expressed by APCs, which bind to CD28 on the T‐cell to provide signal 2. Once activated, T‐cells upregulate CTLA‐4, which competes with CD28 for CD80 and CD86, and conveys a negative signal, acting as a brake to T‐cell activation. The cytokine environment determines T‐cell differentiation. Thus, transforming growth factor‐beta (TGF‐β) favours regulatory T‐cells, gamma‐interferon (IFN‐γ) and interleukin (IL)‐12 TH1 T‐cells, IL‐4 TH2 T‐cells and a mixture of cytokines (IL‐23, TGF‐β and IL‐6) TH17 T‐cells (see Figure 24.3). IL‐6 and IL‐21 are required for the differentiation of T follicular helper T–cells (TFH), which guide B‐cell differentiation. Disordered regulation of TH1 and TH17 responses are thought to underpin autoimmunity while abnormal TH
Basic Immunology and the Biologic Era
Inflammation
Activation of the adaptive immune response
Cells of the immune system
T‐cells
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