Cells In Human Autoimmune Diseases Research Articles

Potential of targeting natural killer T cells for the treatment of autoimmune diseases

Natural killer (NK) T cells emerge as unique lymphocytes subsets implicated in the regulation of autoimmunity. Abnormalities in the numbers and functions of NKT cells have been observed in patients with diverse autoimmune diseases as well as in a variety of mouse strains that are genetically predisposed for the development of autoimmune diseases. Unlike conventional T cells that recognize peptides in association with major histocompatibility complex (MHC), NKT cells recognize glycolipid antigens presented by the nonpolymorphic MHC class I-like protein, CD1d. Recently, vigorous activation of NKT cells by synthetic glycolipids such as α-galactosylceramide (α-GC) or its sphingosine truncated derivative OCH have been shown to suppress autoimmune diseases such as experimental auto-immune encephalomyelitis (EAE), diabetes in nonobese diabetic (NOD) mice, and collagen-induced arthritis (CIA) by inducing T helper (Th) 2 bias of autoimmune T cells. In this review, we examine the potential roles of NKT cells in the pathogenesis of autoimmune disease regulation, and the recent advances in glycolipid therapy for autoimmune disease models. In addition, we summarize studies suggesting a role for NKT cells in human autoimmune disease, and discuss the potential of targeting NKT cells for the treatment of autoimmunity.

An autoreactive gamma delta TCR derived from a polymyositis lesion.

To investigate the role of gammadelta T cells in human autoimmune disease we expressed and characterized a gammadelta TCR from an autoimmune tissue lesion. The TCR was first identified in a rare form of polymyositis characterized by a monoclonal infiltrate of gammadelta T cells which invaded and destroyed skeletal muscle fibers. The Vgamma1.3-Jgamma1-Cgamma1/Vdelta2-Jdelta3 TCR cDNA of the original muscle invasive gammadelta T cell clone was reconstructed from unrelated cDNA and transfected into the mouse hybridoma BW58alpha(-)beta(-). Appropriate anti-human gammadelta TCR Abs stimulated the TCR transfectants to produce IL-2, thus demonstrating that the human gammadelta TCR functionally interacted with murine signaling components. The transfected Vgamma1.3/Vdelta2 TCR recognized a cytosolic protein expressed in cultured human myoblasts and TE671 rhabdomyosarcoma cells. The Ag was recognized in the absence of presenting cells. Using a panel of control gammadelta TCR transfectants with defined exchanges in different positions of both TCR chains, we showed that the gammadelta TCR recognized its Ag in a TCR complementarity-determining region 3-dependent way. To our knowledge, this is the first example of a molecularly defined gammadelta TCR directly derived from an autoimmune tissue lesion. The strategy used in this study may be applicable to other autoimmune diseases.

Use of soluble peptide-DR4 tetramers to detect synovial T cells specific for cartilage antigens in patients with rheumatoid arthritis.

Considerable evidence indicates that CD4(+) T cells are important in the pathogenesis of rheumatoid arthritis (RA), but the antigens recognized by these T cells in the joints of patients remain unclear. Previous studies have suggested that type II collagen (CII) and human cartilage gp39 (HCgp39) are among the most likely synovial antigens to be involved in T cell stimulation in RA. Furthermore, experiments have defined dominant peptide determinants of these antigens when presented by HLA-DR4, the most important RA-associated HLA type. We used fluorescent, soluble peptide-DR4 complexes (tetramers) to detect synovial CD4(+) T cells reactive with CII and HCgp39 in DR4(+) patients. The CII-DR4 complex bound in a specific manner to CII peptide-reactive T cell hybridomas, but did not stain a detectable fraction of synovial CD4(+) cells. A background percentage of positive cells (<0.2%) was not greater in DR4 (DRB1*0401) patients compared with those without this disease-associated allele. Similar results were obtained with the gp39-DR4 complex for nearly all RA patients. In a small subset of DR4(+) patients, however, the percentage of synovial CD4(+) cells binding this complex was above background and could not be attributed to nonspecific binding. These studies demonstrate the potential for peptide-MHC class II tetramers to be used to track antigen-specific T cells in human autoimmune diseases. Together, the results also suggest that the major oligoclonal CD4(+) T cell expansions present in RA joints are not specific for the dominant CII and HCgp39 determinants.

Prospects of vaccination in autoimmune diseases.

Over the past several years, intensive efforts have been directed to define the pathogenic mechanisms and explore the potential immunotherapy of autoimmune diseases. The advances of molecular genetics and cellular immunology have now permitted select experimental immunotherapy using synthetic peptides, T cell receptor idiotypes and monoclonal antibodies. There remain many obstacles for success. First, the T cell receptor usage of autoreactive T cells in human autoimmune diseases are more heterogeneous than animal models. Clearly, there may not be an oligoclonal derivation of T cells in humans with autoimmune diseases. We foresee that the following studies might contribute to further understand pathogenic mechanisms and design feasible immunotherapy: (1) detailed characterizations of self-antigen specific T cell clones; (2) definition of interactions between MHC molecules and T cell receptors at the molecular level; (3) identification and elution of relevant disease inducing self-peptides complexed with MHC molecules and (4) identification of relevant genes that predispose to autoimmunity.