Elsevier

Current Opinion in Immunology

Volume 13, Issue 6, 1 December 2001, Pages 663-669
Current Opinion in Immunology

Review
Effector lymphocytes in autoimmunity

https://doi.org/10.1016/S0952-7915(01)00276-XGet rights and content

Abstract

Autoimmune diseases result from complex interactions among different T- and B-lymphocyte subpopulations that target a rapidly growing number of autoantigens on different cell types. The etiology of most spontaneous autoimmune disorders, and both the kinetics and hierarchy of the underlying autoimmune responses are poorly understood. However, important advances have been made in recent years in our understanding of how autoreactive lymphocytes cause tissue damage, including the discovery that granzyme B binds to a cell surface receptor on target cells. This review is an attempt to summarize recent developments in this area.

Introduction

Most autoimmune disorders arise when cells of specific tissues become the targets of autoantibodies and/or T lymphocytes. In some instances, T lymphocytes effect tissue damage directly through processes of cell-mediated cytotoxicity that involve Fas, perforin, or both. Perforin-mediated lysis requires a cognate interaction between the antigen-specific TCR on a T lymphocyte and the specific antigen (usually a peptide) presented on an MHC molecule on the target cell's plasma membrane (Fig. 1). Fas-mediated cytotoxicity involves the ligation of Fas on the target cell by Fas ligand (FasL) on T cells but does not require a cognate interaction between the effector lymphocyte and its target, and thus has the potential to damage innocent bystanders (Fig. 1).

In other instances, T lymphocytes kill their targets by secreting cytokines that can ligate pro-apoptotic receptors on the target cell (Fig. 1). And yet in other instances, autoreactive lymphocytes kill their targets indirectly, by enhancing their susceptibility to death-effector mechanisms mediated by non-lymphocytes (Fig. 1), by promoting the recruitment of additional inflammatory cells into the target tissue (i.e. cytotoxic macrophages) (Fig. 1), or by driving the differentiation of autoreactive B cells into autoantibody-secreting plasma cells.

This review is an attempt to summarize recent developments in this area.

Section snippets

Effector lymphocytes in autoimmune disorders

Much of what is currently known about effector pathways of autoimmunity has been learned from a handful of spontaneous and experimental models of autoimmune disease. Type 1 diabetes mellitus (T1D) in non-obese diabetic (NOD) mice is a prototypic model of spontaneous, organ-specific autoimmunity. NOD mice spontaneously develop a form of autoimmune diabetes, closely resembling human T1D, that results from destruction of the pancreatic β cells by T lymphocytes.

Fig. 1 provides a simplified overview

Fas versus the granule exocytosis pathways

CTLs can directly kill target cells via two pathways of cell-mediated cytotoxicity: in the perforin pathway, cell death is caused by the direct effects of perforin and a series of serine proteases (granzymes) on the target cell; in the Fas pathway, a T-cell ligand (FasL) binds a target cell receptor (Fas) that induces apoptosis when ligated. Despite numerous studies, the roles of Fas and perforin in T1D remain unclear.

On the one hand, perforin-deficient NOD mice develop insulitis (islet

Conclusions

The effector mechanisms of tissue destruction in auto-immunity are highly complex and involve several immune cell types, antigenic specificities and pathways of cell- and cytokine-mediated cytotoxicity. The importance of a given pathway in a given autoimmune disease is influenced by a number of factors, including the nature of target autoantigens, the type of effector lymphocytes involved and the genetic background of the affected individuals or animal models. This complexity is probably

Acknowledgements

I thank the members of my laboratory for many exciting discussions and D Minardi for secretarial assistance. I regret that I could not cite all literature relevant to this review, owing to space limitations. The work of my laboratory is supported by grants from the Canadian Institutes of Health Research, the Canadian Diabetes Association, and the Juvenile Diabetes Research Foundation.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • •of special interest

  • ••of outstanding interest

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