Pathogenesis Of Organ-specific Autoimmune Diseases Research Articles

STAT3 deficiency in B cells exacerbates uveitis by promoting expansion of pathogenic lymphocytes and suppressing regulatory B cells (Bregs) and Tregs

STAT3 transcription factor induces differentiation of naïve T cells into Th17 cells and loss of STAT3 in T cell prevents development of CNS autoimmune diseases. However, function of STAT3 in the B lymphocyte subset is not well understood. In this study, we have generated mice lacking STAT3 in CD19+ B cells (CD19-STAT3KO) and investigated intrinsic and extrinsic functions of STAT3 in B cells and its potential role in resistance or pathogenesis of organ-specific autoimmune diseases. We show that STAT3 regulates metabolic mechanisms in B cells with implications for bioenergetic and metabolic pathways that control cellular homeostasis in B cells. Thus, loss of STAT3 in CD19-STAT3KO cells perturbed growth and apoptosis by inducing rapid entry of B cells into the S-phase of the cell cycle, decreasing expression of cyclin-dependent kinase inhibitors and upregulating pro-apoptotic proteins. We further show that the CD19-STAT3KO mice develop severe experimental autoimmune uveitis (EAU), an animal model of human uveitis. Exacerbated uveitis in CD19-STAT3KO mice derived in part from enhanced expression of costimulatory molecules on B cells, marked increase of Th17 responses and increased recruitment of granulocytes into the neuroretina. The enhanced autoimmunity upon deletion of STAT3 in B cells is also recapitulated in experimental autoimmune encephalitis, a mouse model of multiple sclerosis and thus support our conclusion that STAT3 deletion in B cells enhanced inflammation and the effects observed are not model specific. Our data further indicate that STAT3 pathway modulates interactions between B and T cells during EAU resulting in alteration of lymphocyte repertoire by increasing levels of autoreactive pathogenic T cells while suppressing development and/or expansion of immune-suppressive lymphocytes (Bregs and Tregs). Taken together, STAT3 exerts diametrically opposite effects in lymphocytes, with loss of STAT3 in B cells exacerbating uveitis whereas Stat3 deletion in T cells confers protection.

Immunopathogenesis of membranous nephropathy: an update

Membranous nephropathy (MN) is a non-inflammatory organ-specific autoimmune disease which affects the kidney glomerulus, resulting in the formation of immune deposits on the outer aspect of the glomerular basement membrane, complement-mediated proteinuria, and severe renal failure in 30% of patients. In the last 10 years, substantial advances have been made in the understanding of the molecular bases of MN, with the identification of several antigens and predisposing genes in children and adults. These ground-breaking findings already have a major impact on diagnosis and monitoring and to some extent on therapies. However, there is evidence that the disease is more complex and involves a variety of antigen-antibody systems and genes involved in immune response, progression, recovery, and protective mechanisms. We herein review these recent findings which open new perspectives of research. Understanding the complex pathogenesis of MN will offer many opportunities for future therapeutic interventions and will hopefully have a major impact on patient care. New insights into the molecular mechanisms of MN may also enlighten the pathogenesis of organ-specific autoimmune diseases.

T helper cells plasticity in inflammation

CD4+ T cells can be subdivided from a functional point of view into two main subsets: effector cells, which provide protection against exogenous offending agents, and regulatory T (Treg) cells whose function is to avoid autoimmune reactions and to stop the effector response against exogenous antigens, when the response itself becomes dangerous for the host. Human effector CD4+ T lymphocytes can be additionally classified into lineages based mainly on their immunological functions that are supported by distinct profile of cytokine, transcription factor, and homing receptors expression. In the last years, beyond the well known populations of human T helper (Th) lymphocytes, Th1 and Th2 cells, other populations have been discovered and phenotypically characterized. These include the Th17 subset, which is certainly the most intensively studied, but also Th22, Th9, and T follicular helper (Tfh) lymphocytes. In addition to their protective functions, these T helper populations are also involved in the pathogenesis of several inflammatory immune-mediated disorders. Th1 and Th17 cells are involved in the pathogenesis of organ-specific autoimmune diseases and other chronic inflammatory disorders, whereas allergen-specific Th2 lymphocytes play a crucial role in allergy. Although classically viewed as distinct lineages, recent evidence indicate that CD4+ T cells, particularly the Th17 subset, are more plastic than previously thought. It is not fully understood how often such plasticity occurs in the course of physiologic responses to pathogens and what its importance is in protective immunity, but in inflammatory conditions Th17 lymphocytes that have shifted towards a Th1 or Th2 phenotype, acquiring the ability to produce IFN-γ or IL-4, and seem to be particularly aggressive and more pathogenic than the unshifted cells. In this context, the possibility to interfere with this modulation of phenotype can be considered a possible target for developing novel therapeutic strategies in the above mentioned diseases.

Novel IL27p28/IL12p40 Cytokine Suppressed Experimental Autoimmune Uveitis by Inhibiting Autoreactive Th1/Th17 Cells and Promoting Expansion of Regulatory T Cells

IL-12 family cytokines are important in host immunity. Whereas some members (IL-12, IL-23) play crucial roles in pathogenesis of organ-specific autoimmune diseases by inducing the differentiation of Th1 and Th17 lymphocytes, others (IL-27 and IL-35) suppress inflammatory responses and limit tissue injury induced by these T cell subsets. In this study, we have genetically engineered a novel IL27p28/IL12p40 heterodimeric cytokine (p28/p40) that antagonizes signaling downstream of the gp130 receptor. We investigated whether p28/p40 can be used to ameliorate uveitis, a CNS inflammatory disease. Experimental autoimmune uveitis (EAU) is the mouse model of human uveitis and is mediated by Th1 and Th17 cells. We show here that p28/p40 suppressed EAU by inhibiting the differentiation and inflammatory responses of Th1 and Th17 cells while promoting expansion of IL-10(+)- and Foxp3(+)-expressing regulatory T cells. Lymph node cells from mice treated with p28/p40 blocked adoptive transfer of EAU to naïve syngeneic mice by immunopathogenic T cells and suppressive effects of p28/p40 derived in part from antagonizing STAT1 and STAT3 pathways induced by IL-27 and IL-6. Interestingly, IL27p28 also suppressed EAU, but to a lesser extent than p28/p40. The inhibition of uveitogenic lymphocyte proliferation and suppression of EAU by p28/p40 and IL27p28 establish efficacy of single chain and heterodimeric IL-12 family cytokines in treatment of a CNS autoimmune disease. Creation of the biologically active p28/p40 heterodimeric cytokine represents an important proof-of-concept experiment, suggesting that cytokines comprising unique IL-12 α- and β-subunit pairing may exist in nature and may constitute a new class of therapeutic cytokines.

Autoimmune hepatitis and antigen-specific T regulatory cells: When can we send in the regulators?

Autoimmune hepatitis and antigen-specific T regulatory cells: When can we send in the regulators?

Induction, function and regulation of IL‐17‐producing T cells

Recent reports have provided convincing evidence that IL-17-producing T cells play a key role in the pathogenesis of organ-specific autoimmune diseases, a function previously attributed exclusively to IFN-gamma-secreting Th1 cells. Furthermore, it appears that IL-17-producing T cells can also function with Th1 cells to mediate protective immunity to pathogens. Although much of the focus has been on IL-17-secreting CD4+ T cells, termed Th17 cells, CD8+ T cells, gammadelta T cells and NKT cells are also capable of secreting IL-17. The differentiation of Th17 cells from naïve T cells appears to involve signals from TGF-beta, IL-6, IL-21, IL-1beta and IL-23. Furthermore, IL-1alpha or IL-1beta in synergy with IL-23 can promote IL-17 secretion from memory T cells. The induction or function of Th17 cells is regulated by cytokines secreted by the other major subtypes of T cells, including IFN-gamma, IL-4, IL-10 and at high concentrations, TGF-beta. The main function of IL-17-secreting T cells is to mediate inflammation, by stimulating production of inflammatory cytokines, such as TNF-alpha, IL-1beta and IL-6, and inflammatory chemokines that promote the recruitment of neutrophils and macrophages.

Essential roles of IL‐12 and dendritic cells but not IL‐23 and macrophages in lupus‐like diseases initiated by cell surface HSP gp96

Proinflammatory cytokine IL-23 but not IL-12 is critical for the pathogenesis of organ-specific autoimmune diseases including experimental autoimmune encephalitis and collagen-induced arthritis. The contribution by IL-23 in systemic autoimmune diseases such as lupus is undefined. We addressed this question in a murine lupus-like disease model, initiated by enforced cell-surface expression of an ER HSP gp96 in C57BL/6 background. We found a significant increase of p40 in the sera in these mice that preceded the onset of diseases. However, autoimmunity was abrogated in transgenic mice expressing membrane-bound gp96 reconstituted with p35-/- BM, but not with p19-/- BM. Moreover, we found that dendritic cells (DC) but not macrophages were the main producers of p40. To dissect the roles of DC further, we depleted DC using a diphtheria toxin-based inducible DC depletion system. We demonstrated that the integrity of DC was essential for autoimmunity. Our results thus revealed that IL-12 and DC are critical for the pathogenesis of lupus-like disease precipitated by cell surface gp96. This study further highlighted the significant biological differences between IL-12 and IL-23.

Interleukin (IL)-12-Driven Primary Hypothyroidism: the Contrasting Roles of Two Th1 Cytokines (IL-12 and Interferon-γ)

IL-12, a prototypic T helper 1 cytokine, has been implicated in the pathogenesis of organ-specific autoimmune diseases, such as Hashimoto's thyroiditis, but reported to give conflicting results in murine models of lymphocytic thyroiditis. To determine the effects of chronic, local production of IL-12 within the thyroid gland, we created transgenic mice that express IL-12 p70 under the transcriptional control of the thyroglobulin promoter. Transgenics developed growth retardation, moderate primary hypothyroidism, and mild lymphocytic infiltration of the thyroid gland. The hypothyroidism was associated with increased mRNA levels of the sodium-iodide symporter, an increase partly due to a direct effect of IL-12 on the thyrocyte. Upon immunization with a suboptimal dose of mouse thyroglobulin, IL-12 transgenic mice developed a lymphocytic thyroiditis that was more frequent and severe than that observed in wild-type littermates. The disease-promoting effect of IL-12 was independent of interferon-gamma, as shown by the similar interferon-gamma levels in transgenics and controls. These findings highlight the contrasting roles of two T helper 1 cytokines and report a novel role of IL-12 on thyroid hormonogenesis.

Regulation of Apoptosis in Endocrine Autoimmunity

Dysregulation of apoptosis is associated with the pathogenesis of organ-specific autoimmune diseases, through altered target organ susceptibility. Apoptosis signaling pathways can be initiated through activation of death receptors such as Fas. A comparative analysis of the expression of Fas and FasL, the antiapoptotic molecule Bcl-2, and apoptosis in both thyrocytes and thyroid-infiltrating lymphocytes (TILs) from patients with either Graves' disease (GD) or Hashimoto's thyroiditis (HT) was performed. GD thyrocytes expressed less Fas than HT thyrocytes, whereas GD TILs had higher levels of Fas and FasL than HT TILs. GD thyrocytes expressed higher levels of Bcl-2 compared with HT thyrocytes. The opposite pattern was observed in GD (low Bcl-2) and HT (high Bcl-2) TILs. Consistently, thyrocyte apoptosis was marked in HT and poor in GD thyroids, and TIL apoptosis was marked in GD and poor in HT. Our findings suggest that in GD thyroid the regulation of Fas/FasL/Bcl-2 favors apoptosis of infiltrating lymphocytes. Moreover, the reduced levels of Fas/FasL and increased levels of Bcl-2 should favor thyrocyte survival and hypertrophy associated with stimulatory thyroid-stimulating hormone receptor antibodies. In contrast, the regulation of Fas/FasL/Bcl-2 expression in HT can promote thyrocyte apoptosis via homophylic Fas-FasL interactions, and a gradual reduction in thyrocyte numbers leading to hypothyroidism. Fas-mediated apoptosis may be a general mechanism of cell damage in destructive organ-specific autoimmunity.

High IFN-α expression is associated with the induction of experimental autoimmune uveitis (EAU) in Fischer 344 rat

Th1-response plays a crucial role in determining pathogenesis of organ-specific autoimmune diseases. It is believed that both IL-12 and INF-α are initiators to regulate Th1- response. In our experimental autoimmune uveitis (EAU) model, both Lewis and Fischer 344 rats share the same MHC class II molecules, while Lewis rat is EAU susceptible and Fischer 344 rat is EAU resistant. However, under the same condition of immunization, if pertussis toxin (PTX) was injected intraperitoneally as an additional adjuvant, Fischer 344 rat can develop EAU. In this study we investigate which mechanisms are involved in the induction of EAU in CFA+R16+PTX-treated (CRP-treated) Fischer 344 rats. In vivo and in vitro data demonstrated that Th1-cytokine, IFN-γ mRNA expression was significantly increased in disease target tissue-eyes and in draining lymph node cells of CRP-treated Fischer 344 rat. When IL-12 and IFN-α mRNA expression were compared in the experimental groups, only IFN-α mRNA expression was associated with EAU development. To distinguish the sources of IFN-α producing cells, it was observed that IFN-α expression was mainly produced by macrophages. It was further confirmed that normal macrophage from Fischer 344 rat was able to produce significant IFN-α in the presence of PTX. The data strongly suggested that IFN-α might be involved in initiating Th1-cell differentiation and in turn contribute to the induction of EAU. High IFN-a expression induced by PTX may represent a novel pathway to initiate Th1 response in Fischer 344 rat.

High IFN-alpha expression is associated with the induction of experimental autoimmune uveitis (EAU) in Fischer 344 rat.

Th1-response plays a crucial role in determining pathogenesis of organ-specific autoimmune diseases. It is believed that both IL-12 and INF-alpha are initiators to regulate Th1-response. In our experimental autoimmune uveitis (EAU) model, both Lewis and Fischer 344 rats share the same MHC class II molecules, while Lewis rat is EAU susceptible and Fischer 344 rat is EAU resistant. However, under the same condition of immunization, if pertussis toxin (PTX) was injected intraperitoneally as an additional adjuvant, Fischer 344 rat can develop EAU. In this study we investigate which mechanisms are involved in the induction of EAU in CFA+R16+PTX-treated (CRP-treated) Fischer 344 rats. In vivo and in vitro data demonstrated that Th1-cytokine, IFN-gamma mRNA expression was significantly increased in disease target tissue-eyes and in draining lymph node cells of CRP-treated Fischer 344 rat. When IL-12 and IFN-alpha mRNA expression were compared in the experimental groups, only IFN-alpha mRNA expression was associated with EAU development. To distinguish the sources of IFN-alpha producing cells, it was observed that IFN-alpha expression was mainly produced by macrophages. It was further confirmed that normal macrophage from Fischer 344 rat was able to produce significant IFN-alpha in the presence of PTX. The data strongly suggested that IFN-alpha might be involved in initiating Th1-cell differentiation and in turn contribute to the induction of EAU. High IFN-alpha expression induced by PTX may represent a novel pathway to initiate Th1 response in Fischer 344 rat.

Role of autoreactive CD8+ T cells in organ-specific autoimmune diseases: insight from transgenic mouse models.

There is now convincing evidence that autoreactive CD8+ T cells can contribute to the pathogenesis of organ-specific autoimmune diseases. In the non-obese diabetic mouse, there is direct evidence that beta-islet cell-specific CD8+ cytotoxic T cells have a pathogenic effect. In human diseases such as autoimmune diabetes and multiple sclerosis, indirect evidence also suggests a role for CD8+ T cells in tissue damage, although their antigen specificity is unknown. Transgenic mouse models as well as the use of knockout mice have been instrumental in the identification of the role of autoreactive CD8+ T cells. Spontaneous models of CD8+ T-cell-mediated autoimmunity generated through transgenesis should help delineate the effector mechanisms leading to tissue destruction. The study of autoreactive CD8+ T cells and the characterization of their antigenic specificity should help unravel the pathophysiology of organ-specific autoimmune diseases, help identify exacerbating foreign antigens, and allow the design of antigen-specific immunotherapy targeting the pathogenic autoreactive T cells.

The Role of Fas-mediated Apoptosis in Thyroid Autoimmune Disease

Apoptosis is a carefully regulated mechanism of cell death that differs from necrosis and plays an important role in normal tissue development and homeostasis, as well as disease processes. Apoptosis also plays an important role in autoimmunity. Defective apoptosis can cause systemic autoimmunity by allowing the survival of autoreactive lymphocytes. It may also be involved in the pathogenesis of organ-specific autoimmune diseases, such as Hashimoto's thyroiditis, through altered target organ susceptibility. Apoptosis signaling pathways can be initiated through activation of death receptors. One of these pathways employs the death receptor Fas and its ligand (FasL). Fas expression and death pathway signaling have been demonstrated in the thyroid, but there is controversy surrounding the expression of FasL and its role in thyroid autoimmunity. A number of proteins, including FAP-1, Bcl-2 and I-FLICE may regulate the Fas pathway in the thyroid and provide potential mechanisms for modifying the pathogenesis of autoimmune thyroid disease.

Organ-specific autoimmunity

The list of organ-specific autoimmune diseases (AID) is expanding. This is particularly true for T-cell-mediated AID, the pathophysiology of which has largely been ignored until recently. The best arguments for T-cell involvement in AID, although indirect, are the presence of a local T-cell infiltrate and the dramatic sensitivity of the disease to T-cell-selective immunosuppressive agents (e.g. cyclosporin A) as in the case of insulin-dependent (type I) diabetes mellitus (IDDM) and psoriasis. This paper will review current questions concerning the etiology and pathogenesis of organ-specific AID.

Th1 and Th2 CD4 + T cells in the pathogenesis of organ-specific autoimmune diseases

CD4 + T cells play a key role in regulating immune system function. When these regulatory processes go awry, organ-specific autoimmune diseases may develop. Here, Roland Liblau, Steven Singer and Hugh McDevitt explore the thesis that a particular subset of CD4 + T cells, namely T helper 1 (Th1) cells, contributes to the pathogenesis of organ-specifc autoimmune diseases, while another subset, Th2 cells, prevents them.