Analysis of Th1/Th2 T-cell subsets.

Specific immune responses are mediated by activated CD4+ T-helper (Th) cells. Two major subsets, denoted Th1 and Th2, have been identified that are characterized by their distinctive cytokine secretion pattern and associated effector functions. The signature cytokines of Th1 and Th2 cells are interferon-gamma and interleukin-4, respectively.

T cell activation as starter and motor of rheumatic inflammation.

Rheumatic inflammation is driven by sustained specific immunity against self-antigens, resulting in local inflammation and cellular infiltration and, subsequently, in tissue damage. Although the specific autoantigen(s) eliciting the detrimental immune reactions in rheumatic diseases have rarely been defined, it has become clear that the mechanisms resulting in the destruction of tissue and the loss of organ function during the course of the diseases are essentially the same as in protective immunity against invasive microorganisms. Of fundamental importance in initiating, controlling, and driving these specific immune responses are CD4 T cells.

Association of the IL4R single-nucleotide polymorphism I50V with rapidly erosive rheumatoid arthritis.

Objective: To examine whether single-nucleotide polymorphisms (SNPs) of the interleukin-4 receptor gene IL4R influence susceptibility to, or radiographic progression in, rheumatoid arthritis (RA).

Methods: The contribution of 2 SNPs (I50V and Q551R) in the coding region of IL4R to RA susceptibility was analyzed by allele-specific polymerase chain reaction in a case-control study of 471 RA patients and 371 healthy controls. Patients with available radiographs of the hands and feet obtained 2 years after disease onset (n = 302) were stratified retrospectively according to radiologic outcome into an erosive and a nonerosive group to evaluate the association between IL4R SNPs and disease progression.

IFNGR1 single nucleotide polymorphisms in rheumatoid arthritis.

On the basis of their biological function, potential genetic candidates for susceptibility to rheumatoid arthritis can be postulated. IFNGR1, encoding the ligand-binding chain of the receptor for interferon gamma, IFNgammaR1, is one such gene because interferon gamma is involved in the pathogenesis of the disease. In the coding sequence of IFNGR1, two nucleotide positions have been described to be polymorphic in the Japanese population.

The p38 mitogen-activated protein kinase signaling cascade in CD4 T cells.

Since the identification of the p38 mitogen-activated protein kinase (MAPK) as a key signal-transducing molecule in the expression of the proinflammatory cytokine tumor necrosis factor (TNF) more than 10 years ago, huge efforts have been made to develop inhibitors of p38 MAPK with the intent to modulate unwanted TNF activity in diseases such as autoimmune diseases or sepsis. However, despite some anti-inflammatory effects in animal models, no p38 MAPK inhibitor has yet demonstrated clinical efficacy in human autoimmune disorders. One possible reason for this paradox might relate to the fact that the p38 MAPK signaling cascade is involved in the functional regulation of several different cell types that all contribute to the complex pathogenesis of human autoimmune diseases.

The p38 mitogen-activated protein kinase regulates effector functions of primary human CD4 T cells.

The role of p38 mitogen-activated protein kinase in primary human T cells is incompletely understood. We analyzed in detail the role of p38 in the regulation of effector functions and differentiation of human CD4 T cells by using a p38-specific inhibitor and a dominant-negative mutant of p38. p38 was found to mediate expression of IL-10 and the Th2 cytokines IL-4, IL-5, and IL-13 in both, primary naive and memory T cells.

The IL-4 receptor alpha-chain-binding cytokines, IL-4 and IL-13, induce forkhead box P3-expressing CD25+CD4+ regulatory T cells from CD25-CD4+ precursors.

The mechanisms underlying the extrathymic generation of CD25+CD4 regulatory T cells (Tregs) are largely unknown. In this study the IL-4R alpha-chain-binding cytokines, IL-4 and IL-13, were identified as inducers of CD25+ Tregs from peripheral CD25-CD4 naive T cells. IL-4-induced CD25+ Tregs phenotypically and functionally resemble naturally occurring Tregs in that they are anergic to mitogenic stimulation, inhibit the proliferation of autologous responder T cells, express high levels of the Forkhead box P3 and the surface receptors glucocorticoid-induced TNFR family-related protein and CTLA-4, and inhibit effector T cells in a contact-dependent, but cytokine-independent, manner.

The role of the T cell in autoimmune inflammation.

T cells, in particular CD4+ T cells, have been implicated in mediating many aspects of autoimmune inflammation. However, current evidence suggests that the role played by CD4+ T cells in the development of rheumatoid inflammation exceeds that of activated proinflammatory T-helper (Th)1 effector cells that drive the chronic autoimmune response. Subsets of CD4+ T cells with regulatory capacity, such as CD25+ regulatory T (Treg) cells and Th2 cells, have been identified, and recent observations suggest that in rheumatoid arthritis the function of these regulatory T cells is severely impaired.

Generation and regulation of human Th1-biased immune responses in vivo: a critical role for IL-4 and IL-10.

Tissue damage in many human autoimmune diseases is mediated by activated autoantigen-specific Th1 cells. Delineation of the regulatory mechanisms controlling a Th1-biased human immune reaction and its pathologic potential is, therefore, a critical step in the understanding of autoimmune diseases. In this study, we introduce a novel means to investigate human Th1-biased immune responses in vivo.

GATA-3 in human T cell helper type 2 development.

The delineation of the in vivo role of GATA-3 in human T cell differentiation is a critical step in the understanding of molecular mechanisms directing human immune responses. We examined T cell differentiation and T cell-mediated effector functions in individuals lacking one functional GATA-3 allele. CD4 T cells from GATA-3+/- individuals expressed significantly reduced levels of GATA-3, associated with markedly decreased T helper cell (Th)2 frequencies in vivo and in vitro.

Restriction of de novo pyrimidine biosynthesis inhibits Th1 cell activation and promotes Th2 cell differentiation.

Leflunomide, an inhibitor of de novo pyrimidine biosynthesis, has recently been introduced as a treatment for rheumatoid arthritis in an attempt to ameliorate inflammation by inhibiting lymphocyte activation. Although the immunosuppressive ability of leflunomide has been well described in several experimental animal models, the precise effects of a limited pyrimidine supply on T cell differentiation and effector functions have not been elucidated. We investigated the impact of restricted pyrimidine biosynthesis on the activation and differentiation of CD4 T cells in vivo and in vitro.

The balance of Th1/Th2 cytokines in rheumatoid arthritis.

It has been suggested that rheumatoid inflammation is mediated by activated pro-inflammatory T helper type I cells. In contrast, immunomodulatory T helper type 2 cells and their cytokines, in particular interleukin-4, are rarely found. This chapter reviews the concept of the Th1/Th2 dichotomy and summarizes the functions of the signature cytokines of the T helper subsets.

Antigen-independent Th2 cell differentiation by stimulation of CD28: regulation via IL-4 gene expression and mitogen-activated protein kinase activation.

To delineate the molecular mechanisms regulating Th2 cell differentiation, CD28-mediated generation of Th2 effectors was analyzed. In the absence of TCR ligation CD28 stimulation induced Th2 differentiation of memory but not of naive CD4(+) T cells, whereas costimulation via CD28 and the TCR enhanced Th2 differentiation from naive T cells but suppressed it from memory T cells. Stimulation of T cells via the CD28 pathway, therefore, provided critical signals facilitating Th2 cell differentiation.