T cells play a central role in chronic immunologic dis eases in which inflammation is a prominent component. Many of the newly developed therapies that have shown efficacy in such diseases are drugs that inhibit the recruitment and activities of T cells.

Etiology of T Cell–Mediated Diseases

 The major causes of T cell–mediated hypersensitivity reactions are autoimmunity and exaggerated or persistent responses to microbial or other environmental antigens. The autoimmune reactions usually are directed against cellular antigens with restricted tissue distribution. Therefore, T cell–mediated autoimmune diseases tend to be limited to a few organs and usually are not systemic. Examples of T cell–mediated hypersensitivity reactions against environmental antigens include contact sensitivity to chemicals (e.g., various therapeutic drugs and substances found in plants such as poison ivy). Tissue injury also may accompany T cell responses to microbes. For example, in tuberculosis, a T cell–mediated immune response develops against protein antigens of Mycobacterium tuberculosis, and the response becomes chronic because the infection is difficult to eradicate. The resultant granulomatous inflammation causes injury to normal tissues at the site of infection.

Excessive polyclonal T cell activation by certain microbial toxins produced by some bacteria and viruses can lead to production of large amounts of inflammatory cytokines, causing a syndrome similar to septic shock. These toxins are called superantigens because they stimulate large numbers of T cells. Superantigens bind to invariant parts of T cell receptors on many different clones of T cells, regardless of antigen specificity, thereby activating these cells. 

Mechanisms of Tissue Injury

In different T cell–mediated diseases, tissue injury is caused by inflammation induced by cytokines that are produced mainly by CD4+ T cells or by killing of host cells by CD8+ cytotoxic T lymphocytes (CTLs) (Fig. 1). These mechanisms of tissue injury are the same as the mechanisms used by T cells to eliminate cell-associated microbes.

Fig1. Mechanisms of T cell–mediated tissue injury (type IV hypersensitivity). T cells may cause tissue injury and disease by two mechanisms. A, Inflammation may be triggered by cytokines produced mainly by CD4+ T cells in which tissue injury is caused by activated macrophages and inflammatory cells. B, Direct killing of target cells is mediated by CD8+ cytotoxic T lymphocytes (CTLs). APC, Antigen-presenting cell.

CD4+ T cells may react against cell or tissue antigens and secrete cytokines that induce local inflammation and activate macrophages. Different diseases may be associated with activation of Th1 and Th17 cells. Th1 cells are the source of interferon-γ (IFN-γ), the principal macrophage-activating cytokine, and Th17 cells are responsible for the recruitment of leukocytes, including neutrophils. The actual tissue injury in these diseases is caused mainly by the macrophages and neutrophils.

The typical reaction mediated by T cell cytokines is delayed-type hypersensitivity (DTH), so called because it occurs 24 to 48 hours after an individual previously exposed to a protein antigen is challenged with the antigen (i.e., the reaction is delayed). The delay occurs because it takes several hours for circulating effector T lymphocytes to home to the site of antigen challenge, respond to the antigen at this site, and secrete cytokines that induce a detectable reaction. DTH reactions are manifested by infiltrates of T cells and blood monocytes in the tissues (Fig. 2), edema and fibrin deposition caused by increased vascular permeability in response to cytokines produced by CD4+ T cells, and tissue damage induced by leukocyte products, mainly from macrophages that are activated by the T cells. DTH reactions often are used to determine if people have been previously exposed to and have responded to an antigen. For example, a DTH reaction to a mycobacterial antigen, PPD (purified protein derivative), applied to the skin, is an indicator of past or active mycobacterial infection.

Fig2. Delayed-type hypersensitivity reaction in the skin. A, Perivascular accumulation (cuffing) of mononuclear inflammatory cells (lymphocytes and macrophages), with associated dermal edema and fibrin deposition. B, Immunoperoxidase staining reveals a predominantly perivascular cellular infiltrate that marks positively with anti-CD4 antibodies. (B, Courtesy Dr. Louis Picker, Department of Pathology, Oregon Health Sciences University, Portland, OR.)

CD8+ T cells specific for antigens on host cells may directly kill these cells. CD8+ T cells also produce cytokines, including IFN-γ that may induce inflammation in some hypersensitivity diseases. In many T cell–mediated autoimmune diseases, both CD4+ T cells and CD8+ T cells specific for self-antigens are present, and both contribute to tissue injury. 

 Clinical Syndromes and Therapy

 Many organ-specific autoimmune diseases in humans are believed to be caused by T cells, based on the identification of these cells in lesions and similarities with animal models in which the diseases are known to be T cell mediated (Fig. 3). These disorders typically are chronic and progressive, in part because long-lived memory T cells are generated, and the inciting anti gens, such as tissue antigens or proteins expressed by resident microbes, are often never cleared. Also, tissue injury causes release and alteration of self-proteins, which may result in reactions against these newly encountered proteins. This phenomenon has been called epitope spreading to indicate that the initial immune response against one or a few self-antigen epi topes may spread to include responses against many more self-antigens.

Fig3. T cell–mediated diseases. Diseases in which T cells play a dominant role in causing tissue injury; antibodies and immune complexes may also contribute. Note that multiple sclerosis, rheumatoid arthritis, and type 1 diabetes are autoimmune disorders. Crohn disease, an inflammatory bowel disease, is likely caused by reactions against microbes in the intestine and may have a component of autoimmunity. The other diseases are caused by reactions against foreign (microbial or environmental) antigens. In most of these diseases, the role of T cells is inferred from the detection and isolation of T cells reactive with various antigens from the blood or lesions, and from the similarity with experimental models in which the involvement of T cells has been established by a variety of approaches. The specificity of pathogenic T cells has been defined in animal models and in some of the human diseases. Viral hepatitis and toxic shock syndrome are disorders in which T cells play an important pathogenic role, but these are not considered examples of hypersensitivity. CTL, Cytotoxic T lymphocyte; DTH, delayed-type hypersensitivity; HBV, hepatitis B virus; HCV, hepatitis C virus.

The therapy for T cell–mediated hypersensitivity dis orders is designed to reduce inflammation and to inhibit T cell responses. The mainstay of treatment of such dis eases has been the potent antiinflammatory steroids, but these drugs have significant side effects. The development of more targeted therapies based on understanding of the fundamental mechanisms of these diseases has been one of the most impressive accomplishments of immunology. Antagonists of inflammatory cytokines have proved to be very effective in patients with various inflammatory and autoimmune diseases. For example, monoclonal antibodies that block TNF or IL-6 receptor, and small molecule inhibitors of the inflammatory cytokine signaling molecule Janus kinase 3 (JAK3), are now used to treat rheumatoid arthritis, and IL-17 blocking antibodies are used to treat psoriasis. Other agents developed to inhibit T cell responses include drugs that block costimulators such as B7. Clinical trials are underway to test the efficacy of transferring in vitro expanded Tregs and administering IL-2 to expand endogenous Tregs for the treatment of autoimmune diseases such as type 1 diabetes and lupus. There also is active research on methods for inducing tolerance in pathogenic T cells. 

مواضيع ذات صلة

Congenital Immunodeficiencies: Defects in Lymphocyte Maturation

Congenital Immunodeficiencies: Defects in Innate Immunity

Congenital (Primary) Immunodeficiencies

Neuroimmunology: Interactions Between the Immune and Nervous Systems

Disorders of Neutrophils

Cell Surface Receptors

Sepsis

Acute Inflammation

Etiology, Examples, and Therapy of Immune Complex–Mediated Diseases

Examples and Treatment of Diseases Caused by Cell- or Tissue-Specific Antibodies

Mechanisms of Antibody-Mediated Tissue Injury and Disease

Hypersensitivity Disorders Caused by Immune Responses : Clinical Syndromes and Therapy