Rheumatoid Arthritis: Goronzy JJ

Weyand CM, Goronzy JJ, Kurtin PJ. · No affiliation provided · Arthritis Rheum. · Pubmed #16508924 links to  free full text

This publication has no abstract.

Goronzy JJ, Weyand CM. · Departments of Medicine and Immunology, Mayo Clinic, Rochester, MN, USA. · Arthritis Res Ther. · Pubmed #12723978 links to  free full text

Abstract: Depleting B cells with anti-CD20 monoclonal antibodies emerges as a new therapeutic strategy in autoimmune diseases. Preliminary clinical studies suggest therapeutic benefits in patients with classic autoantibody-mediated syndromes, such as autoimmune cytopenias. Treatment responses in rheumatoid arthritis have opened the discussion about whether mechanisms beyond the removal of potentially pathogenic antibodies are effective in B-cell depletion. B cells may modulate T-cell activity through capturing and presenting antigens or may participate in the neogenesis of lymphoid microstructures that amplify and deviate immune responses. Studies exploring which mechanisms are functional in which subset of patients hold the promise of providing new and rational treatment approaches for autoimmune syndromes.

Suzuki M, Konya C, Goronzy JJ, Weyand CM. · The Kathleen B. and Mason I. Lowance Center for Human Immunology and Rheumatology, Emory University, Atlanta, GA, USA. · Hum Immunol. · Pubmed #18812196 No free full text.

Abstract: Rheumatologists have long been focused on developing novel immunotherapeutic agents to manage such prototypic autoimmune diseases as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The ultimate challenge in providing immunosuppressive treatment for patients with RA and SLE has derived from the dilemma that both protective and harmful immune responses result from adaptive immune responses, mediated by highly diverse, antigen-specific T and B cells endowed with powerful effector functions and the ability for long-lasting memory. As regulatory/suppressor T cells can suppress immunity against any antigen, including self-antigens, they emerge as an ideal therapeutic target. Several distinct subtypes of CD8(+) suppressor cells (Ts) have been described that could find application in treating RA or SLE. In a xenograft model of human synovium, CD8(+)CD28(-)CD56(+) T cells effectively suppressed rheumatoid inflammation. Underlying mechanisms involve conditioning of antigen presenting cells (APC). Adoptively transferred CD8(+) T cells characterized by IL-16 secretion have also exhibited disease-inhibitory effects. In mice with polyarthritis, CD8(+) Ts suppressed inflammation by IFNgamma-mediated modulation of the tryptophan metabolism in APC. In SLE animal models, CD8(+) Ts induced by a synthetic peptide exerted suppressive activity mainly via the TGFbeta-Foxp3-PD1 pathway. CD8(+) Ts induced by histone peptides were found to downregulate disease activity by secreting TGFbeta. In essence, disease-specific approaches may be necessary to identify CD8(+) Ts optimally suited to treat immune dysfunctions in different autoimmune syndromes.

Diaz-Borjon A, Weyand CM, Goronzy JJ. · Kathleen B. and Mason I. Lowance Center for Human Immunology, Department of Medicine, Emory University School of Medicine, 101 Woodruff Circle, Atlanta, GA 30322, USA. · Exp Gerontol. · Pubmed #17125948 links to  free full text

Abstract: The treatment armamentarium in rheumatic inflammatory diseases has drastically increased in the last years. Earlier uses of conventional disease-modifying antirheumatic drugs (DMARDs), along with the arrival of newer therapies including the so-called "biologic" agents, have provided better long-term outcomes for patients suffering from these illnesses. Biologic agents have shown efficacy for several diseases and failed in others. Due to a high prevalence of some of these diseases in the elderly population, this age group may also benefit, although treatment will have to be tailored to its special needs. In this mini review, we will discuss the use of these medications in rheumatic diseases with a significant prevalence in the elderly, their proven and potential uses, and the considerations that need to be taken into account when using them in this population.

Weyand CM, Goronzy JJ. · Kathleen B and Mason I Lowance Center for Human Immunology, Department of Medicine, Emory School of Medicine, Atlanta, GA 30322, USA. · Nat Clin Pract Rheumatol. · Pubmed #16932686 No free full text.

Abstract: T cells regulate the disease process in rheumatoid arthritis (RA) on multiple levels and represent a logical choice for anti-inflammatory therapy. In the inflamed joint they promote neoangiogenesis and lymphoid organogenesis, and stimulate synoviocyte proliferation and development of bone-eroding osteoclasts. The design of T-cell-targeted therapies for RA needs to take into account the uniqueness of T-cell generation, turnover and differentiation in affected patients. Patients accumulate 'old' T cells that respond to alternate regulatory signals because of an accelerated immune aging process; any therapeutic interventions that increase the replicative stress of T cells should, therefore, be avoided. Instead, therapeutic approaches that raise the threshold for T-cell activation are more promising. As a rule, antigen-derived signals synergize with co-stimulatory signals to stimulate T cells; such co-stimulatory signals are now targeted in novel immunosuppressive therapies. An example is abatacept (soluble cytotoxic-T-lymphocyte-associated protein 4-immunoglobulin), which binds with high affinity to CD80/CD86 and effectively suppresses inflammatory activity in RA. The therapeutic benefits gained by disrupting T-cell co-stimulation indicate that the pathogenesis of RA is driven by a more generalized abnormality in T-cell activation thresholds rather than a highly selective action of arthritogenic antigens.

Goronzy JJ, Henel G, Sawai H, Singh K, Lee EB, Pryshchep S, Weyand CM. · Kathleen B. and Mason I. Lowance Center for Human Immunology, Emory University School of Medicine, Rm. 1003, Woodruff Memorial Research Bldg., 101 Woodruff Circle, Atlanta, GA 30322, USA. · Ann N Y Acad Sci. · Pubmed #16461801 No free full text.

Abstract: The pathogenesis of rheumatoid arthritis (RA) is determined by a complex interaction of genetic and environmental factors. Of all risk factors, age has the largest impact. RA occurs most often during the postmenopausal period of life, with incidence rates peaking in the eighth decade. While age is generally accepted as an etiologic factor for failure of immunocompetence, much less is understood about the role of T-cell senescence in autoimmunity. We have hypothesized that senescent T cells are particularly prone to be activated in specialized microenvironments, such as the synovial membrane. CD4 T cells in the senescence program were identified by the loss of CD28. Gene expression profiling documented that CD28- T cells have acquired a spectrum of regulatory receptors that are usually seen only on NK cells. Such regulatory receptors include stimulatory and inhibitory members of the killer immunoglobulin-like receptor (KIR) family, the stimulatory c-type lectin receptor NKG2D, and CX3CR1, the receptor for the chemokine fractalkine. Synovial fibroblasts express the relevant ligands, thus providing stimulatory signals to tissue-infiltrating T cells. The signaling pathways of these regulatory receptors are complex and dependent on the individual T cells, some of which express important adapter molecules such as DAP10 and DAP12. Inhibitory KIRs on T cells are often only partially functional. Our data suggest that, by virtue of altered receptor profiles, conventional tolerance mechanisms can be evaded in the aging host. By acquiring a new set of regulatory receptors, senescent CD4 T cells become responsive to novel environmental cues and find ideal stimulatory conditions in the synovial microenvironment.

Weyand CM, Seyler TM, Goronzy JJ. · Lowance Center for Human Immunology, Emory University School of Medicine, Atlanta, Georgia, USA. · Arthritis Res Ther. · Pubmed #15960820 No free full text.

Abstract: In rheumatoid arthritis, T cells, B cells, macrophages, and dendritic cells invade the synovial membranes, establishing complex microstructures that promote inflammatory/tissue destructive lesions. B cell involvement has been considered to be limited to autoantibody production. However, recent studies suggest that B cells support rheumatoid disease through other mechanisms. A critical element of rheumatoid synovitis is the process of ectopic lymphoid neogenesis, with highly efficient lymphoid architectures established in a nonlymphoid tissue site. Rheumatoid synovitis recapitulates the pathways of lymph node formation, and B cells play a key role in this process. Furthermore, studies of rheumatoid lesions implanted in immunodeficient mice suggest that T cell activation in synovitis is B cell dependent, indicating the role played by B cells in presenting antigens and providing survival signals.

Park YW, Pryshchep S, Seyler TM, Goronzy JJ, Weyand CM. · Department of Medicine, Lowance Center for Human Immunology, Emory University School of Medicine, Woodruff Memorial Research Building, 101 Woodruff Circle, Atlanta, GA 30322, USA. · Expert Opin Ther Targets. · Pubmed #15948665 No free full text.

Abstract: Historically, the pathogenic role of B cells in autoimmune disease has been attributed to the formation of autoantibodies which, as soluble immunoglobulins or immunocomplexes, can trigger cellular damage and initiate the inflammatory cascade. Recent results from clinical trials applying B cell-directed therapeutics in rheumatoid arthritis and systemic lupus erythematosus have challenged such traditional views and encouraged novel ideas about the disease involvement of B cells. Suppression of disease activity, often disconnected from effects on autoantibody titers, has supported the notion that B cells may promote autoimmune disease by serving as antigen-presenting cells that sustain T cell activation. Likewise, B cells have been implicated in supporting the process of ectopic lymphoid neogenesis, a mechanism that stabilises pathogenic immune responses in target tissues and thus contributes to disease chronicity. As a general rule, clinical effects of B cell-directed therapeutics have often been unanticipated and unpredicted by experimental models, emphasis-ing the need to explore and verify disease principles in the patient.

Goronzy JJ, Weyand CM. · Department of Medicine, Kathleen B. and Mason I. Lowance Center for Human Immunology, Emory School of Medicine, Atlanta, GA 30322, USA. · Immunol Rev. · Pubmed #15790350 No free full text.

Abstract: Therapeutic efficacy of depleting B cells or blocking T-cell costimulation in rheumatoid arthritis (RA) has confirmed the critical pathogenic role of adaptive immune responses. Yet, RA preferentially affects elderly individuals, in whom adaptive immunity to exogenous antigens begins to fail. Here, we propose that senescence of the immune system is a risk factor for RA, with chronic inflammation resulting from the accumulation of degenerate T cells that have a low threshold for activation and utilize a spectrum of novel receptors to respond to microenvironmental cues. The process of immunosenescence is accelerated in RA and precedes the onset of disease, the acceleration, in part, being conferred by the HLA-DR4 haplotype. Naive CD4(+) T cells in RA are contracted in diversity and restricted in clonal burst. Senescence of effector CD4(+) T cells is associated with the loss of CD28 and the de novo expression of KIR2DS2, NKG2D, and CX(3)CR1, all of which function as costimulatory molecules and reduce the threshold for T-cell activation. The synovial microenvironment promotes chronic persistent immune responses by facilitating ectopic lymphoid neogenesis, such as the formation of aberrant germinal centers. With the propensity to develop complex lymphoid architectures and to provide optimal activation conditions for senescent CD4(+) T cells, the synovium becomes a natural target for pathogenic immune responses in prematurely aged individuals.

Weyand CM, Goronzy JJ. · Department of Medicine, Kathleen B. and Mason I. Lowance Center for Human Immunology, Emory School of Medicine, 101 Woodruff Circle, Atlanta, GA 30322, USA. · Trends Mol Med. · Pubmed #15350894 No free full text.

This publication has no abstract.

Goronzy JJ, Weyand CM. · Lowance Center for Human Immunology, Emory University School of Medicine, 1364 Clifton Road NE, Atlanta, GA 30322, USA. · Curr Opin Rheumatol. · Pubmed #15103247 No free full text.

Abstract: PURPOSE OF REVIEW: Rheumatoid arthritis (RA) is characterized by a chronic T-cell response that has escaped normal control mechanisms. This review summarizes recent insights in pathways that are functional in RA and that favor continuous and pathogenic T-cell activation. RECENT FINDINGS: T-cell activation is ultimately determined by positive signals from costimulatory molecules and negative signals from regulatory T cells. Blockade of the classic costimulatory pathway, CD28-CD80 or CD86, is beneficial in RA. Additional pathways that predominantly control the activation of memory and effector T cells are functionally important in synovial inflammation. Some of these costimulatory molecules (such as stimulatory killer cell immunoglobulin-like receptors and NKG2D) appear to be relatively specific for RA and not to play a role in normal immune responses. In addition to this predominance of positive signals, age-disproportionate decline in thymic activity in RA may lead to a diminution of regulatory T cells and loss of their negative signals. SUMMARY: The successful treatment trial of RA with CTLA-4Ig clearly documents the importance of T-cell costimulation in RA disease activity. Novel costimulatory pathways may be of even greater significance than CD28 in RA and may represent promising new therapeutic targets. The finding of reduced thymic activity in RA is exciting and will stimulate further studies of T-cell homeostasis and the function of regulatory cells.

Goronzy JJ, Weyand CM. · Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA. · Arthritis Res Ther. · Pubmed #12932282 links to  free full text

Abstract: Rheumatoid arthritis (RA), like many other autoimmune syndromes, is a disease of adults, with the highest incidence rates reported in the elderly. The immune system undergoes profound changes with advancing age that are beginning to be understood and that need to be incorporated into the pathogenetic models of RA. The age-related decline in thymic function causes extensive remodeling of the T-cell system. Age-dependent changes in T-cell homeostasis are accelerated in patients with RA. The repertoire of naive and memory T cells is less diverse, possibly as a result of thymic insufficiency, and it is biased towards autoreactive cells. Presenescent T cells emerge that are resistant to apoptosis and that often expand to large clonal populations. These cells are under the regulatory control of nonconventional costimulatory molecules, display potent effector functions, and appear to be critical in the synovial and extra-articular manifestations of RA.

Weyand CM, Fulbright JW, Goronzy JJ. · Department of Medicine and Immunology, Mayo Clinic, Guggenheim 401, 200 First Street SW, Rochester, MN 55905, USA. · Exp Gerontol. · Pubmed #12915205 No free full text.

Abstract: Current disease models of autoimmune syndromes, such as rheumatoid arthritis, propose that chronic inflammation is caused by 'forbidden T-cell clones' that recognize disease-inducing antigens and drive tissue-injurious immune reactions. Reappraisal of disease incidence data, however, emphasizes that rheumatoid arthritis is a syndrome of the elderly that occurs with highest likelihood in individuals in whom the processes of T-cell generation and T-cell repertoire formation are compromised. Thymic T-cell production declines rapidly with advancing age. Multiple mechanisms, including antigen-driven clonal expansion and homeostasis-driven autoproliferation of post-thymic T cells, impose replicative stress on T cells and induce the biological program of cellular senescence. T-cell immunosenescence is associated with profound changes in T-cell functional profile and leads to accumulation of CD4+ T cells that have lost CD28 but have gained killer immunoglobulin-like receptors and cytolytic capability and produce large amounts of interferon-gamma. In patients with rheumatoid arthritis, T-cell immunosenescence occurs prematurely, probably due to a deficiency in the ability to generate sufficient numbers of novel T cells. We propose that autoimmunity in rheumatoid arthritis is a consequence of immunodegeneration that is associated with age-inappropriate remodeling of the T-cell pool.

Weyand CM, Goronzy JJ. · Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA. · Ann N Y Acad Sci. · Pubmed #12727633 No free full text.

Abstract: Synovial inflammation in rheumatoid arthritis is closely related to the formation of ectopic lymphoid microstructures. In synovial tissue from some patients, one finds seemingly diffuse infiltrates; in others, T cells and B cells cluster in aggregates with interdigitating dendritic cells (DCs) but no follicular DCs (FDCs). In a third group, T cell/B cell follicles with germinal center (GC) reactions are generated. Within a given patient, aggregates and GCs are mutually exclusive and stable over time. Because antigen storage capacity, lymphoid density, and three-dimensional topography of GCs optimize immune responses, synovial GCs should play a crucial role in the breakdown of self-tolerance. We have identified factors critical for ectopic GCs, thereby transforming the synovial inflammatory process. Tissues with GCs produced 10- to 20-fold higher amounts of the chemokines CXCL13 and CCL21. CXCL13 derived from three sources, endothelial cells, synovial fibroblasts, and FDC networks. The level of CXCL13 transcripts strongly predicted GCs; however, some tissues had high levels of CXCL13 but lacked GCs. Tissue expression of LT-beta emerged as a second key factor. LT-beta protein was detected on follicular center and mantle zone B cells. Multivariate regression analysis identified CXCL13 and LT-beta as the only cytokines predicting GCs. Remarkably, LT-alpha did not contribute independently. The contribution of B cells to ectopic lymphoid organogenesis was not limited to LT-beta production. Rather, synovial tissue B cells were critical in regulating T cell activation. In adoptive transfer experiments in human synovium-SCID mouse chimeras, activation of synovium-derived CD4 T cells was strictly dependent on T cell/B cell follicles. Depletion of synovial tissue B cells abrogated T cell function, and non-B cell antigen-presenting cells could not maintain T cell stimulation. Unexpectedly, GC function in the rheumatoid lesion was also dependent on CD8 T cells. The majority of T cell receptors derived from CD8 T cells were shared between distinct GCs. Depletion of CD8 T cells disrupted synovial GCs, FDC networks disappeared, and transcription of LT-beta, IgG, and Igkappa declined. Follicle-sustaining CD8 T cells were located at the edge of or within the mantle zone. Cell-cell communication in the mantle zone, including CD8 T cells, appears to be critical for ectopic GC formation in rheumatoid synovitis.

Weyand CM, Kang YM, Kurtin PJ, Goronzy JJ. · Departments of Medicine and Immunology, Mayo Clinic Rochester, Rochester, Minnesota 55905, USA. · Curr Opin Rheumatol. · Pubmed #12707579 No free full text.

Abstract: Lymphoid organs are the anatomic solution to the challenge of responding to minute amounts of antigen with powerful effector mechanisms. By arranging interacting cells in complex three-dimensional topographies lymphoid organs provide an optimal match between form and function. This principle is exploited in ectopic lymphoid structures that characteristically appear in rheumatoid synovitis. Synovial tissue T cells and B cells cooperate in different types of lymphoid organizations. Dendritic cell networks in the inflamed synovial membrane optimize antigen collection, storage, processing, and presentation. Synovial tissue cells participate in lymphocyte recruitment and the formation of tissue architectures that amplify immune responses. Recent data support the concept that the tissue organization in the rheumatoid joint fosters a breakdown in self-tolerance by promoting a phase transition from self-limited immune responses to self-perpetuating autoimmune responses.

Weyand CM, Braun A, Takemura S, Goronzy JJ. · Departments of Medicine/Rheumatology and Immunology, Mayo Clinic and Foundation, Rochester, Minn., USA. · Curr Dir Autoimmun. · Pubmed #11791464 No free full text.

This publication has no abstract.

Goronzy JJ, Weyand CM. · Departments of Medicine/Rheumatology, and Immunology, Mayo Clinic and Foundation, Rochester, Minn., USA. · Curr Dir Autoimmun. · Pubmed #11791462 No free full text.

This publication has no abstract.

Weyand CM, Goronzy JJ, Liuzzo G, Kopecky SL, Holmes DR, Frye RL. · Division of Rheumatology and Internal Medicine, Mayo Clinic, Rochester, Minn 55905, USA. · Mayo Clin Proc. · Pubmed #11605685 No free full text.

Abstract: Acute coronary syndromes (ACS) are complications of atherosclerotic vascular disease that are triggered by the sudden rupture of an atheroma. Atherosclerotic plaque stability is determined by multiple factors, of which immune and inflammatory pathways are critical. Unstable plaque is characterized by an infiltrate of T cells and macrophages, thereby resembling a delayed hypersensitivity reaction. On activation, T cells secrete cytokines that regulate the activity of macrophages, or the T cells may differentiate into effector cells with tissue-damaging potential. Constitutive stimulation of T cells and macrophages in ACS is not limited to the vascular lesion but also involves peripheral immune cells, suggesting fundamental abnormalities in homeostatic mechanisms that control the assembly, turnover, and diversity of the immune system as a whole. This review gives particular attention to the emergence of a specialized T-cell subset, natural killer T cells, in patients with ACS. Natural killer T cells have proinflammatory properties and the capability of directly contributing to vascular injury.

Klimiuk PA, Weyand CM, Sierakowski S, Goronzy JJ. · Klinika Reumatologii i Chorób Wewnetrznych Akademii Medycznej w Białymstoku. · Postepy Hig Med Dosw. · Pubmed #11227380 No free full text.

Abstract: The diagnostic category of rheumatoid arthritis, a syndrome of chronic inflammatory disease of the synovial membrane and of extraarticular tissues, covers a broad spectrum of clinical phenotypes. Here we propose that distinct combinations of disease risk genes produce heterogeneity of rheumatoid disease. Recognition of this genetic and clinical heterogeneity has immediate implications as it provides the opportunity to develop selective therapies for the different variants of disease.

Weyand CM, Bryl E, Goronzy JJ. · Division of Rheumatology, Mayo Foundation, Rochester, MN, USA. · Arch Immunol Ther Exp (Warsz). · Pubmed #11140470 No free full text.

Abstract: In rheumatoid arthritis (RA), T cells infiltrate into the synovial membrane where they initiate and maintain activation of macrophages and synovial fibroblasts, transforming them into tissue-destructive effector cells. The diversity of the disease process and the formation of complex lymphoid microstructures indicate that multiple T cell activation pathways are involved. This model is supported by the association of distinct disease patterns with different variants and combinations of HLA class II molecules. T cell pathology in RA, however, is not limited to the joint. Affected patients have major abnormalities in the T cell pool, with a marked contraction in T cell receptor diversity and an outgrowth of large clonal populations. Clonally expanded CD4+ T cells lose expression of the CD28 molecule and gain expression of perforin and granzyme. Consequently, the functional profile of expanded CD4(+)CD28null T cells is fundamentally changed and is shifted towards tissue-injurious capabilities. CD4(+)CD28null T cells are particularly important in patients with extra-articular manifestations of RA, where they may have a direct role in vascular injury. Understanding the mechanisms underlying the loss of T cell diversity and the emergence of pro-inflammatory CD4(+)CD28null T cell clonotypes may have implications for other autoimmune syndromes.

Weyand CM, Goronzy JJ, Takemura S, Kurtin PJ. · Division of Rheumatology, Mayo Clinic, Rochester, Minnesota 55905, USA. · Arthritis Res. · Pubmed #11094459 links to  free full text

Abstract: In rheumatoid arthritis, T cells and B cells participate in the immune responses evolving in the synovial lesions. Interaction between T cells and B cells is probably antigen specific because complex microstructures typical of secondary lymphoid organs are generated. Differences between patients in forming follicles with germinal centers, T-cell-B-cell aggregates without germinal center reactions, or loosely organized T-cell-B-cell infiltrates might reflect the presence of different antigens or a heterogeneity in host response patterns to immune injury. Tertiary lymphoid microstructures in the rheumatoid lesions can enhance the sensitivity of antigen recognition, optimize the collaboration of immunoregulatory and effector cells, and support the interaction between the tissue site and the aberrant immune response. The molecular basis of lymphoid organogenesis studied in gene-targeted mice will provide clues to why the synovium is a preferred site for tertiary lymphoid tissue. B cells have a critical role in lymphoid organogenesis. Their contribution to synovial inflammation extends beyond antibody secretion and includes the activation and regulation of effector T cells.

Weyand CM, Goronzy JJ. · Department of Medicine, Mayo Clinic Foundation, Rochester, Minnesota 55905, USA. · Arthritis Res. · Pubmed #11094432 links to  free full text

Abstract: Genes in the human leukocyte antigen (HLA) region remain the most powerful disease risk genes in rheumatoid arthritis (RA). Several allelic variants of HLA-DRB1 genes have been associated with RA, supporting a role for T-cell receptor-HLA-antigen interactions in the pathologic process. Disease-associated HLA-DRB1 alleles are similar but not identical and certain allelic variants are preferentially enriched in patient populations with defined clinical characteristics. Also, a gene dosing effect of HLA-DRB1 alleles has been suggested by the accumulation of patients with two RA-associated alleles, especially in patient subsets with a severe disease course. Therefore, polymorphisms in HLA genes are being explored as tools to dissect the clinical heterogeneity of the rheumatoid syndrome. Besides HLA polymorphisms, other risk genes will be helpful in defining genotypic profiles correlating with disease phenotypes. One such phenotype is the type of synovial lesion generated by the patient. HLA genes in conjunction with other genetic determinants may predispose patients to a certain pathway of synovial inflammation. Also, patients may or may not develop extraarticular manifestations, which are critical in determining morbidity and mortality. HLA genes, complemented by other RA risk genes, are likely involved in shaping the T-cell repertoire, including the emergence of an unusual T-cell population characterized by the potential of vascular injury, such as seen in extraarticular RA.

Weyand CM, Goronzy JJ. · Department of Medicine, Mayo Clinic and Foundation, Rochester, MN 55905, USA. · Int Rev Immunol. · Pubmed #10614738 No free full text.

Abstract: A dense infiltrate of activated T cells, macrophages, and B cells in the synovial membrane is the cardinal pathological feature of rheumatoid arthritis (RA). Frequently, tissue infiltrating cells acquire a morphological organization reminiscent of secondary lymphoid tissue. The composition of the inflammatory lesions, the production of autoantibodies, and the association of disease risk with genes related to the HLA-D region have all been cited as evidence for a critical role of T cells in disease pathogenesis. Investigations on the precise role of HLA genes in RA have confirmed the importance of this genetic risk factor and have identified a consensus sequence within the HLA-DRBI genes. The observation that HLA polymorphisms are mostly associated with disease progression and severity and that a gene dose effect for HLA-DR genes is operational has challenged the simple model that HLA molecules select and present an arthritogenic antigen. Studies analyzing the repertoire of tissue infiltrating T cells have not been able to identify a dominant and common disease relevant T cell. The infiltrate is diverse in terms of T cell receptor gene usage but consistently includes clonally expanded populations. Recent evidence indicates that RA patients carry expanded CD4 clonotypes which are characterized by deficient CD28 expression and autoreactivity. These autoreactive CD4 T cells are not restricted to the joint, raising the possibility that rheumatoid synovitis is a manifestation of a systemic autoimmune disease. Support for this model has come from studies in T cell receptor (TCR) transgenic animals which develop inflammation of the synovial membrane stimulated by a T cell response to ubiquitously expressed self-MHC molecules. Antigens driving the chronic persistent immune response in RA may not be restricted to the joint but rather may be widely distributed, providing an explanation for the difficulties in identifying arthritogenic antigens directly or indirectly through the selection of joint infiltrating T cells.

Weyand CM, Goronzy JJ. · Department of Medicine, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA. · Curr Opin Rheumatol. · Pubmed #10328581 No free full text.

Abstract: One manifestation of rheumatoid arthritis (RA) is a destructive inflammation of the joint, but many other organs can be targeted by this disease, classifying it as a truly systemic disorder. Accordingly, pathogenic models have to account for the multiorgan character of RA. This article proposes that the primary abnormalities in RA lie in the assembly of the T-cell pool and in the maintenance of T-cell homeostasis. Evidence has accumulated that the repertoire of CD4 T cells in RA patients is distinct and includes a high frequency of disease-relevant T cells. Emergence of T cells with self-aggressive potential could indicate a failure of negative selection in the thymus. Also, the turnover of mature T cells in the periphery is altered in RA patients with a sharp contraction in diversity. Loss of diversity results from the replacement of rare T-cell specificities by multiplying T-cell clones. Large clonal T-cell populations in RA patients acquire a distinct phenotype (CD4+CD28null) and functional profile (overproduction of interferon-gamma, cytotoxicity), giving them the ability to function as proinflammatory cells. Optimal conditions for T-cell stimulation are encountered in the synovium, where ectopic lymphoid tissue with germinal centers is formed. Considering the systemic nature of RA, therapeutic strategies suppressing synovial inflammation while ignoring systemic abnormalities could lack the potential of a curative intervention.

Lee WW, Yang ZZ, Li G, Weyand CM, Goronzy JJ. · Kathleen B. and Mason I. Lowance Center for Human Immunology, Emory University, Atlanta, GA 30322, USA. · J Immunol. · Pubmed #17675524 links to  free full text

Abstract: Rheumatoid arthritis (RA) is characterized by premature immune aging with accumulation of degenerate T cells deficient for CD28. Gene expression profiling of CD4(+)CD28(-) and CD4(+)CD28(+) T cells to discover disease-promoting activities of CD28(-) T cells identified expression of CD70 as a most striking difference. Hence, CD70 was significantly more expressed in CD4 T cells from RA patients compared with age-matched controls (p < 0.006). The underlying mechanism was a failure to repress CD70 expression after activation-dependent induction. This defect in RA was not related to differential promoter demethylation. CD70 on bystander CD4(+)CD28(-) T cells functioned by lowering the threshold for T cell activation; admixture of CD4(+)CD28(-) T cells augmented TCR-induced responses of autologous naive CD4(+)CD28(+) T cells, particularly of low-avidity T cells. The data support a model in which CD70 expressed on T cells causes degeneracy in T cell responses and undermines tolerance mechanisms that normally control T cell autoreactivity.