Basic Immunology and the Biologic Era

Chapter 24
Basic Immunology and the Biologic Era


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


Inflammation


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.

Image described by caption.

Figure 24.1 Acute inflammation begins within seconds of tissue injury. The local blood vessels dilate and the increase in their permeability leads to the movement of fluid and proteins into the interstitial space. Proinflammatory cytokines upregulate the adhesion molecules, selectins and integrins, on the endothelial cell walls. Leucocytes, predominantly neutrophils, localize to the periphery of the blood vessel (margination). They bind loosely to selectins on the endothelium (tethering) and as these weak bonds are formed and broken, the cells roll along the endothelium. The leucocytes become activated and bind more tightly to integrins on the endothelium (adhesion), a process that is promoted by chemokines. These small, chemoattractant cytokines are produced at the site of inflammation and bind to molecules on the vascular surface of endothelial cells such as heparan sulphate. They thereby form a chemoattractant gradient that leads to activation and egress of leucocytes, which subsequently migrate between the endothelial cells and into the interstitial spaces (diapedesis)


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).

Image described by caption.

Figure 24.2 Chronic inflammation. A key feature of chronic inflammation, shown here in an inflamed joint, is mononuclear cellular infiltration and the activation and proliferation of resident cells which leads to subsequent tissue damage. T‐cell activation by APCs classically occurs in the lymph nodes but APCs are also present in the synovium. The T‐cell response generated is dependent on the cytokine microenvironment. T‐cells subsequently interact with macrophages and B‐cells. Macrophages become activated following their interaction with T‐cells or binding to immune complexes via their Fc‐gamma receptors (FcR). The macrophage moves from its primary role in tissue of ‘guarding’ and ‘scavenging’ debris to secreting a wide range of substances: chemokines for leucocyte recruitment; cytokines; growth factors which, with cytokines, promote angiogenesis; and matrix metalloproteinases which lead to the breakdown of the extracellular matrix. B‐cell activation leads to cytokine release and autoantibody production. The B‐cells also interact bidirectionally with T‐cells, receiving co‐stimulatory help and acting as APCs. BAFF is essential to B‐cell survival. In inflamed tissue, B‐cells may be found in ectopic germinal centres, surrounding follicular dendritic cells. Osteoclasts accumulate in the inflamed synovium adjacent to bone, resulting in bone resorption and structural damage. Binding of RANKL to its receptor, RANK, promotes osteoclast differentation from monocyte precursors. RANKL is produced by activated T‐cells and also from synovial fibrobasts under the influence of proinflammatory cytokines. Fibroblasts in RA are phenotypically different from those in the normal synovium and these changes are induced by the proinflammatory environment. They proliferate to form a ‘quasi‐malignant’ pannus and secrete proinflammatory cytokines, chemokines, VEGF, which promotes angiogenesis, and MMPs which cause tissue breakdown. BAFF, B‐cell activating factor; GMCSF, granulocyte macrophage colony‐stimulating factor; IFN‐γ, gamma interferon; MMP, matrix metalloproteinase; RANKL, receptor activator of nuclear factor kappa‐B ligand; TNF, tumour necrosis factor; VEGF, vascular endothelial growth factor


Activation of the adaptive immune response


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.

Illustration of T helper cell activation, with arrow labeled clonal expansion and differentiation determined by cytokine environment from dendritic cell and cytokines to T-cells (TH1, TH2, TH17, and Treg).

Figure 24.3 T helper cell activation. Antigen‐presenting cells (APCs), shown here as a dendritic cell, detect the pathogen, internalize it and present fragments of denatured proteins and peptides on class II MHC molecules to the T‐cell receptor (TCR) on naive CD4 T‐cells. Engagement of the TCR alone is not sufficient to stimulate the T‐cell and two further signals are required. Signal 2 is provided by co‐stimulatory molecules, e.g. CD28 binding to CD80 or CD86 which promotes T‐cell expansion. Signal 3 is provided primarily by cytokines which direct T‐cell differentiation into the different T‐cell subsets, which each have distinctive cytokine profiles and functions. CD4 on the T‐cell acts as a co‐receptor for the TCR, binding to MHCII


Cells of the immune system


T‐cells


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

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Nov 5, 2018 | Posted by in RHEUMATOLOGY | Comments Off on Basic Immunology and the Biologic Era
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