Scandinavian Journal of Immunology

The Pathogenesis of Rheumatoid Arthritis

Journal:

Scandinavian Journal of Immunology SJI-11-185 Review 20-Jun-2011

Manuscript ID: mstype:

Date Submitted by the Author: Complete List of Authors:

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Keywords:

Rojas Rodrguez, Jorge; Hospital Guadalupe, Puebla, Mxico, Servicio de Reumatologa Garca Carrasco, Mario; Hospital General Regional 36 IMSS, Puebla, Mxico, Unidad de Enfermedades Autoinmunes Sistmicas; Facultad de Medicina, Benemrita Universidad Autnoma de Puebla, Mxico, Departamento de Reumatologa Escobar Linares, Luis; Hospital Guadalupe, Puebla, Mxico, Servicio de Endocrinologa Mendoza Pinto, Claudia; Facultad de Medicina, Benemrita Universidad Autnoma de Puebla, Mxico,, Departamento de Reumatologa; Hospital General Regional 36 IMSS, Puebla, Mxico, Unidad de Enfermedades Autoinmunes Sistmicas Jara Quezada, Luis; Centro Mdico Nacianal La Raza, Mxico., Centro Mdico Nacianal La Raza, Mxico. Rheumatoid Arthritis < Autoimmunity, B Cells < Cells, Natural Killer Cells < Cells, T Cells < Cells, Autoimmunity < Diseases, Adhesion Molecules < Molecules, Cell Surface Molecules < Molecules, Cytokines < Molecules, T Cell Receptors < Molecules, Antigen Presentation/Processing < Processes

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The Pathogenesis of Rheumatoid Arthritis

Jorge Rojas Rodrguez1, Mario Garca Carrasco 2,3, Luis Edgardo Escobar Linares4, Claudia Mendoza Pinto2,3, Luis Javier Jara Quezada5.
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Servicio de Reumatologa del Hospital Guadalupe, Puebla, Mxico; Departamento de Reumatologa, Facultad de Medicina, Benemrita Universidad

Autnoma de Puebla, Mxico

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Unidad de Enfermedades Autoinmunes Sistmicas Hospital General Regional 36 IMSS,

Puebla, Mxico,
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Servicio de Endocrinologa del Hospital Guadalupe, Puebla, Mxico;

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Jefatura del Departamento de Investigacin del Centro Mdico Nacianal La Raza,

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Mxico.

Corresponding Author: Mario Garcia Carrasco, 16 Sur 1314-206, Puebla, Puebla 7200

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Mexico. Email: mgc30591@yahoo.com

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Abstract Rheumatoid arthritis (RA) is a fascinating, tissue-specific, systemic autoimmune disease.. The clinical expression of RA varies widely between individual patients and over time in the same patient. These clinical variations are difficult to explain, but advances in our knowledge of the molecular mechanisms about regulation of interaction of the innate and adaptive immune response provide clues to construct solid concepts on the production of ectopic lymphoid follicles. Similar, the knowledge about the surprisingly-rapid activation of a wide repertoire of signaling pathways that drive the differentiation of a primed T lymphocyte.

Keywords: Rheumatoid arthritis, synovial membrane, pathogenesis

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Introduction Rheumatoid arthritis (RA) is a fascinating, tissue-specific, systemic autoimmune disease. Its pathogenesis consists of several stages that begin with the formation of an ectopic lymph follicle. It happens on synovial membrane where maturing dendritic cells interact with nave (non primed) T helper (Th) CD4 + cells. These dentritic cells have been exported from the bone marrow and arrived through lymphatic vessels to into a tertiary lymphoid organ on the synovial membrane. It is worth mentioning that the microenvironment in synovial membrane has been modified by dendritic and other antigen presenting cells (APC) that express the shared epitope (SE) in their class II major histocompatibility molecule (MHC), which is presented to the T cell antigen receptor (TCR) as an MHC-(antigenic) peptide complex (MHC-peptide) on the APC membrane. The engagement of the TCR and the MHC-antigen-peptide initiates and drives the differentiation of ThCD4+ lymphocytes and shapes the adaptive immune response (1-4). This complex, highly-regulated process constitutes the immunological synapse, and may, within seconds, trigger some effector functions (killer T cells on target cells) through multiple tyrosine phosphorylation mediated signaling pathways on priming T lymphocytes. However, sustained TCR engagement and signaling for many minutes or hours is required for more complex functions, such as T cell proliferation.

Therefore, the priming of ThCD4+ within ectopic lymph follicles of rheumatoid synovitis occurs in a severely-modified microenvironment, where an abundance of proinflammatory signals and the silence of regulatory mechanisms polarize the differentiation of T cells on immunological synapse toward the inflammatory Th1 and Th17 phenotypes. The interaction of TCR with the class II MHC-peptide complex on the surface of APC is not sufficient to induce the development of an effective immune response, and thus

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the engagement of costimulatory molecules is crucial in amplifying and regulating efficient differentiation of T lymphocytes. The positive coreceptor of the CD28 family on T cells and its ligands CD80 (B7.1) and CD86 (B7.2) on APC play an important role in the activation and proliferation of T cells and enhance cytokine production on these cells. In contrast, the negative coreceptor CTLA-4, suppresses T cell activation and down-regulates IL-2 production on T lymphocytes and cycle cell progression, therefore an effective set of costimulatory signals amplifies and regulates an efficient adaptive response (5). This article analyzes the roles of the major contributors to the pathogenesis of RA and the possible sequence of events they participate in order to visualize new therapeutic strategies through intelligent interference with the pathogenic mechanisms.

Rheumatoid Follicle

An ectopic pathogenic lymphoid follicle may be classified as a tertiary lymphoid organ; it is formed of an accumulation of lymphoid cells that arises as a response to environmental stimuli emerging from damaged tissues as a consequence of chronic inflammation due to various causes, especially microbial infection, graft rejection and

autoimmunity (6)

Most patients with RA express the SE, a common aminoacid motif in the third hypervariable region of the -chain on the alleles HLA-DR4, HLA-DR1 and HLA-DR10. The SE may drive a loss of in situ tolerance to self-antigens, inducing the expansion of selfreactive effector cells and providing an appropriate microenvironment where inflammatory APC-derived cytokines polarize T cell differentiation to the Th1 phenotype (7). Dendritic cells detect pathogens via pattern recognition receptors (PRRs) which act as sensors of conserved pathogen molecular microbial patterns (PAMP); PRRs are

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expressed both on plasma membrane as in endosomal or lysosomal organelles; pathogen antigen recognition triggers an intracellular signaling cascade that results in the expression of type I interferons (IFNs) and other inflammatory response genes. IFNs bind receptors on membrane cells to activate JAK-STAT and other signaling pathways that often share common downstream signaling molecules and are interconnected in distinct ways.

Membrane associated PRRs such as Toll-like receptors (TLRs) and C-type lectin receptors (CLRs) on the membrane of maturing DCs recognize extracellular pathogens, while cytosolic PRRs, including retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) and nucleotide-binding domain and leucine-rich-repeat-containing receptors (NLRs). RLRs are expressed by most cell types. RIG-I and melanoma differentiation factor 5 (MDA5) RLR members detect viral RNA through their helicase domain and induce the activation of transcription factors NF-kB and interferon regulatory factor 3 (IRF3) and the nuclear factor of activated T cells (NFAT) mediated by the engagement of mitochondria antiviral signaling protein (MAVS) with RLRs (8). These activating transcription factors-PRRs induce responses in B and T lymphocytes and up-regulate the synthesis of IL-1, IL-6 and other inflammatory cytokines, which act on the immunological synapse, shift differentiation of nave ThCD4+ toward Th1 and Th17CD4+ phenotypes and drive the up-regulation of a highly inflammatory and potentially pathogen adaptive immune response. Toll-like PRRs are also potent regulating factors of CD8+T cell responses (9). High mobility group box 1 nuclear protein (HMGB1) is a constituent of chromatin and the major regulator of inflammation and tissue response to infection and injury through the control of migratory properties of cells such as monocytes, smooth muscle, vesselassociated stem cells, and endothelial progenitor cells (10). HMGB1, once translocated from maturing myeloid dendritic cells to the

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extracellular environment, promotes recruitment and extravasation (migration across the vessel wall) of inflammatory leucocytes via long term activation of nuclear factor B (NFB) (11, 12). Autocrine /paracrine production of HMGB1 by maturing DCs leads to RAGE (receptor for advanced glycation end products) activation and increases the expression of lymph node chemokine receptors on their own membrane. In this fashion, maturing DCs reach secondary lymphoid organs to induce the clonal expansion of Ag-specific T cells

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(13).

Additionally, HMGB1 is incorporated to immune complexes to increase cytokine production through activation of TLR9 (an endosomal-lysosomal Toll-like receptor) and RAGE. The innate immune system recognizes unmethylated CpG dinucleotides, which are relatively common in bacterial and viral genomes, but are highly methylated and uncommon in mammalian genomes. Therefore, vertebrate immune systems display specific Toll-like receptors that distinguish microbial DNA from self-DNA. The expression of Tolllike receptors and their capacity to recognize pathogen molecular patterns varies between species, but the activation of distinct TLR induces similar responses. Therefore, activation of TLR9 by unmethylated CpG dinucleotides promotes Th1 adaptive immune responses through the enhanced expression of costimulatory molecules both in B cells and in plasmacytoid dendritic cells (pDCs), where TLR9 is primarily or exclusively expressed (9, 14-16). Cathepsins are a family of lysosomal cysteine proteases that act as nonspecific scavengers of cellular proteins and play a major role in some cell type specific functions: cathepsins L and S play an important role in the processing, trafficking and maturation of pathogen antigens that bind to MHC class-II will be presented by dendritic cells as a

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complex on their membrane surface at the beginning of immunological synapse to receptor of T lymphocyte. Cathepsin K does not participate in antigen processing, but is highlyexpressed in osteoclasts, enabling them to breakup type I collagen and degrade the bone matrix (17, 18). An unsuspected role of cathepsin K was observed when two groups of rats expressing adjuvant-induced arthritis were treated with either alendronate or a potent cathepsin K inhibitor named NC-2300 administered orally. Radiological analysis revealed that NC-2300, but not alendronate, induced

although the two compounds exhibited a similar capacity to prevent periarticular osteoporosis. Bone erosion is the hallmark of rheumatoid arthritis on radiological images. Thus, it is probable that the acidified microenvironment induced by the activation of HMGB1 and RAGE at the endosome provides suitable conditions to enhance the expression of cathepsin K through the activation of Toll-like receptors, mainly TLR9, which binds CPG (its ligand), increasing the activity of osteoclasts and, therefore, bone erosion and chronic joint damage (17, 18).

Peripheral maturing DCs expressing CCR7 and CXCR4 reach the lymph nodes through afferent lymphatic vessels as response to lymph node chemokines and the isoform of phosphoinositide-kinase, which is essential to the response to chemotactic agonists; this process is increased by lymph vessel chemokines (19). Cells of the innate immune system induce the up-regulation of major histocompatibility complex (MHC) class II and costimulatory molecules (CD80/CD86) through their pattern recognition receptors, activating a cascade of intracellular sequential signals that determine the fate of nave T cell activation (20). Increased mRNA expression of LT, LT, CXCL13, CCL21 and CCR7 in RA tissues containing ectopic lymphoid

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significant suppression of bone erosion,

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structures and the expression of mRNA encoding the LT receptor in rheumatoid synovial tissues have been demonstrate; all these molecules have been implicated in the development of lymph nodes. Therefore, it is probable that activation of TLRs in the synovial membrane of patients who express SE induces enhanced expression of CXCR4 and CXCR5, receptors of the chemokines CXCL12 and CXCL13, respectively, and of the CXCR7 receptor of CXCL19 and CXCL21 (9). These chemokines, which are essential for normal lymph node development, are also produced in rheumatoid synovial membrane to drive ectopic follicle lymphoid neogenesis (6). Peptidylarginine deiminase (PAD; EC 3.5.3.15) mediates the posttranslational deamination of protein-bound arginine to citrulline in histones at the nucleus. The estrogensensitive PADI4 gene is expressed in bloodstream granulocytes (4,5) and in CD34 (+) stem cells of the bone marrow (6). PADI4 encodes peptidylariginine deiminase 4 (PAD type IV), which induces the posttranslational deamination of arginine residues in histones H3 and H4 (21), driving the production of citrulline modified target epitopes that activate the generation of anticyclic citrullinated peptide antibodies (ACPA); these antibodies have been found in the frozen serum samples of healthy individuals, stored for years and analyzed within the first months of rheumatoid arthritis clinical expression. Therefore, they are currently considered the cornerstone of the pathogenesis of RA (22, 23).

The expression of PADI4 does not differ in peripheral leucocytes from RA patients and healthy individuals and, in contrast to leucocytes from rheumatoid synovial follicular centers, do not induce peptide citrullination. It has been demonstrated that ectopic follicular structures of rheumatoid synovitis invariably express activation-induced cytidine deaminase (AID), the enzyme required for

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somatic hypermutation and class switch recombination (CSR) of IgG and IgM genes to promote B cell proliferation and the production of ACPA. In addition, sustained

proliferation of ACPA+CD138+ plasma cells surrounding AID+/CD21+ rheumatoid lymphoid follicles, ongoing CSR and ACPA production has been observed (24). Therefore, it is probable that dendritic cells and other APC residing on a tertiary lymph follicle embedded in synovial membrane of individuals expressing SE recognize citrullinated peptides (CP) as pathogen microbial antigens and activate an adaptive immune response against immune [HMC-(SE)-CP complex. Citrullinated peptides are derived from at least four endogenous (fibrinogen, vimentin, collagen type II and alpha enolase) proteins. Rheumatoid symptoms and clinical manifestations of distinct autoimmune syndromes are expressed by patients with hepatitis C virus (HCV) infection and, less frequently, by people infected by rubella, Epstein-Barr and other viruses. The clinical expression of autoimmunity is triggered or exacerbated in preexisting autoimmune diseases

by viral infections (25).

Dendritic cells and macrophages on synovial membrane follicles in patients with chronic hepatitis C virus infection would also be activated through DAMP (danger or damaged tissue associated molecular patterns) by tissue damage induced by inflammatory cytokines in the presence of the shared epitope to express rheumatoid synovitis. Likewise, it has been suggested that Porphyromonas gingivalis periodontitis infection might activate rheumatoid synovitis in individuals who express the shared epitope. Porphyromonas gingivalis is the only bacterium identified to date that expresses the citrullinated alpha enolase proteins encoded by its own PAD enzyme (26, 27).

Costimulation and regulating factors of the immunological synapse

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The engagement of the membrane-APC class II HMCAg complex with the receptor of priming-T cells at the beginning of the immunological synapse is not sufficient to reap an efficient T cell differentiation, and the engagement of four additional molecules is required: CD80 (B7.1) and CD86 (B7.2) are secreted by dendritic cells to interact with the positive coreceptor CD28 and CTLA-4 a negative coreceptor secreted by priming T cells at the immunological synapse. CD28 expressed by most nave ThCD4+ induces T cell proliferation and up-regulates IL-2 synthesis and other inflammatory cytokines on dendritic cells. Cytotoxic T lymphocyte antigen (CTLA-4) also binds CD80 and CD86 on APC membrane to suppress the activity of its homologue, CD28. Therefore, CTLA-4 inhibits IL2 production, prevents IL-2 receptor (IL-2R) expression and down-regulates cell cycle progression and T cell activation (5).

It has been demonstrated that CTLA-4 induces the differentiation of priming lymphocytes toward antigen-specific CD4+ CD25+ Foxp3+ and CD4+ CD 25- TGF-1+

adaptive regulatory T cells phenotypes (28).

Dendritic cells are endowed to trigger the lineage priming process of ThCD4+ nave cells just at the moment of cell division; when asymmetric distribution of regulatory proteins in daughter cells provides the opportunity to induce and regulate the expression of different gene patterns on successive gene programs. The expression of DC-derived cytokines controls the activity of stage-specific networks of transcriptional factors, shifting differentiation of naive T cells to regulatory T cells that prevent autoimmunity or, as a result of specific microenvironmental conditions, polarize differentiation of T cells into Th17 cells, which are the prototypical phenotype of proinflammatory cytokine-producing-Th cells. This apparently paradoxical double role of APC-derived cytokines is crucial to obtain an efficient adaptive immune response. It has been demonstrated that inefficient DC

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induced-Th17 cell differentiation on mesenteric lymph nodes may be reverted, suppressing the activity of DC-retinoic acid in animal models. This vitamin A metabolite is a key regulator of transforming growth factor- (TGF-), the cytokine that promotes differentiation of nave T cells into regulatory Tregs, but in presence of IL-6 on microenvironment, TGF- drives differentiation to proinflammatory Th17 cell phenotype. Therefore, DC and other cells of the innate immune response are endowed with great ductility and a high capacity to respond rapidly and efficiently to changing stimuli from the microenvironment through the production of cytokines and the expression of PPRs to recognize PAMP, DAMP and chemokines; this microenvironment is ongoing regulated by physiological signals such as hormones and neurotransmitters acting on a sequential or recurrent fashion to induce an efficient adaptive response. Therefore, the lineage of T cells is a fascinating process which can stop and go back or trigger specific transduction pathway signals emerging from the innate immune system to induce and drive the adaptive immune response. The subsequent stages of this process require the epigenetic activation or repression of genes over a dynamic process suitable to choose a specific pathway (29, 30). The lineage of priming ThCD4+ cells is regulated at both the transcriptional and epigenetic level to become Th1, Th2 or Th17 effector cells or might likewise choose to become antigen-specific regulatory cells. This process is the hallmark of the adaptive immune response; it occurs within lymph nodes and secondary lymphoid organs. Increasing data support the concept that priming of nave ThCD4+ cells on tertiary lymphoid organs is up-regulated by CD28-dependent activation of HMGB1 on maturing dendritic cells through increased production of IL-2 and RAGE-induced inflammatory pathways of the innate immune system that eventually lead to selective proliferation and differentiation of B lymphocytes into mature autoantibody-secreting cells as occurs in the rheumatoid synovial

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membrane, the salivary glands in Sjgrens syndrome and the thyroid gland in Hashimoto disease (31). IMMUNENEURO-ENDOCRINE ARTHRITIS. Since some decades ago, it has been evident that patients with RA show multiple disturbances of the immune-neuro-endocrine system. Hypothalamus-Pituitary-Adrenal axis (HPA). The initial studies were done at experimental level in which it was demonstrated that susceptibility of Lewis rats to an inflammatory/ autoimmune disease similar to RA is due, at least in part, to an abnormal response in the HPA axis (32). In RA patients, cortisol levels similar to control subjects have been found, even in the presence of high pro-inflammatory cytokine levels, which represent an inefficient response from the start of the disease (33, 34). These alterations are mediated by hypothalamic and pituitary hormones, and pro-inflammatory cytokines, such as IL-6 and TNF-A recent study showed that patients with good response to anti-TNF- treatment also presented an increase in serum cortisol levels in contrast with the patients with poor response. This study demonstrated for the first time that in humans, inflammation induced by TNF-interferes with HPA axis integrity and correlates with treatment response. Determination of plasmatic cortisol may be a sensitive marker to predict response to anti TNF-treatment (35). Hypothalamus-Pituitary-Gonadal Axis (HPG). In patients with RA, an abnormal metabolism of sex hormones has been demonstrated systemically and locally (in synovial fluid). Low serum concentrations of T, dehydrotestosterone, DHEA and INTERACTION IN RHEUMATOID

dehydroepiandrosterone sulfate (DHEAS) have been found, while E levels are normal or even high (36). Men with RA, including patients older than 50 years, had mean T levels

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lower than controls early in the course of the disease, suggesting mild hypogonadotropic hypogonadism. In patients who responded to treatment, T levels increased significantly. A decrease in DAS28 during the 2 year follow-up significantly correlated with increased T levels (37). A subset of glucocorticoid-nave premenopausal females with RA has a relative hypocompetence of adrenocortical function with low levels of basal cortisol, and DHEAS and alterations in adrenal synthetic pathways or deficiencies in steroidogenesis (38). The imbalance in E metabolism results in an elevation of 16-hydroxiestrone/4hydroxiestradiol metabolites (39). These hydroxilated E metabolites have the ability to stimulate monocyte proliferation and growth, and to play a role in synovial hyperplasia (40). These disturbances may be attributed to the fact that TNF-, IL-1, and IL-6 stimulate aromatase activity, partially explaining the abnormal peripheral synthesis of E in RA and their increased availability in the synovial fluid (41). Synovial cells express E receptors that correlate positively with synovial secretion of IL-6 and IL-8 (42). Therapeutic blocking of TNF- increase DHEAS levels, suggesting that biologic therapy may improve HPG axis function (43).

Autonomic Nervous System (ANS). Activation of sympathetic nervous system (SNS) and parasympathetic nervous system in RA occurs parallel to the HPA axis activation and to the cytokines, hormones and neuro-transmitters expression. This hypothesis is based on experimental models. In the arthritis model induced by type II collagen, it has been found that transient increase of cortisol is followed by an increase in adrenaline levels and hypothalamic overexpression of IL-1 and IL-6 during the arthritis induction phase. The symptomatic phase showed hypothalamic noradrenaline increase followed by loss of noradrenergic fibers in joints. These findings indicate a disruption of the immune-neuroendocrine communication and noradrenergic activity during experimental arthritis (44).

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Patients with juvenile idiopathic arthritis (JIA), have an increase in SNS tone. This data shows that patients with JIA have an altered function of the ANS associated with increased central noradrenergic outflow, presumably leading to increased vasoconstriction, resulting in a decreased response to an orthostatic stressor (45). Patients with early RA have high cardiac SNS activity while the parasympathetic activity is normal. These results suggest that inflammatory stress is responsible for these derangements in patients with RA (46). Tissue with inflammation from RA patients had less sympathetic nervous fibers in comparison with patients with osteoarthritis or trauma. Sensory nerve fibers contain two major neuropeptides, substance P (SP) and calcitonin gene-related peptide (CGRP). The pro-inflammatory role of SP is known, while CGRP has anti-inflammatory activities. In RA, there is an increase in sensory fibers, SP, and a decrease in sensory fibers for the peptide related with CGRP in comparison with osteoarthritis (47, 48). Some markers of SNS activity in patients with RA have been identified. Semaphorin 3C, a factor directed against sympathetic nervous fibers seems to be the principal responsible for reduction of tissue innervations in RA (49). Soluble neuropilin, a nerve repellent receptor, is another responsible for the disappearance of sympathetic nerve fibers soon after the beginning of inflammation (50). There are high levels of adrenal chromographin A in RA patients (51). Activation of SNS has pro and anti-inflammatory effects, depending on the stage of the inflammatory process and the stimulated receptors. The acute phase of RA is characterized by -adrenoreceptors stimulation with pro-inflammatory effects, whereas the chronic stage discloses stimulation of -adrenoreceptors with anti-inflammatory effects (52). The increased activation of ANS influences in a negative way the RA course participating in the increase of cardiovascular risk observed in RA patients. Early detection of SNS hyperactivity in RA patients may be noteworthy to prevent these complications. In this

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regard, neuropeptide Y (NPY), an excellent indicator of sympathetic activity, is increased in patients with RA and SLE and could be used as a sympathetic hyperactivity marker [53]. However, another study found that NPY levels did not differ between RA and control group or in heart rate variability parameters considered to reflect sympathetic activity (54).

Prolactin-Growth Hormone system. (PRL-GH). The first evidences of PRL role in arthritis were found in children with juvenile chronic arthritis with positive antinuclear antibodies who had significant PRL increase in direct correlation with IL-6 serum levels (55, 56). It was found a correlation among increased PRL levels, clinical activity and macrophage activity indicators such as 1 inflammatory chemokine (MIP-1) (57). An interesting study in males with RA found that high PRL levels were associated with long-term RA and a poor functional class (58). These findings have been confirmed and they are associated with RA activity as well (59). PRL levels in synovial fluid from RA patients are similar to those of patients with osteoarthritis, but GH and other gonadal hormones and neuropeptides, were elevated in the synovial fluid of these patients suggesting a local pro-inflammatory role of these hormones (60). One of the first hormonal functional studies demonstrated that post-menopausal women with RA developed HPRL and a dissociation of the ACTH response after stimulation with TRH and CRH, respectively, independent of clinical activity (61).This derangement is more evident in HLA-DR4+ patients than in HLA-DR4- patients suggesting an alteration of HPA and PRL release in RA (62). Another study demonstrated that RA patients secreted

excessive amounts of PRL during a stressful situation like surgery in comparison with chronic osteomyelitis patients. High PRL levels may contribute to disease activity increasing the inflammatory/immune process regardless of genetic factors (63). However,

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in patients with recent RA diagnosis and without steroid treatment or remission induction drugs, there was no difference in ACTH, cortisol, PRL and TSH serum concentrations in the controls, before and after the stimulation with their respective hypothalamic releasing hormones (64). Other studies employed insulin induced hypoglycemia stress test in order to measure cortisol, TRH and PRL in active RA patients without steroids, demonstrating a HPA axis dysfunction and normal PRL release (65). Another investigation found that PRL and GH response to hypoglycemia stress was similar in RA under treatment and controls (66), although the receiver operating characteristic (ROC) curve analysis of PRL secretion was minor in RA patients. Other authors using the same stimulus found a diminished PRL response in patients with non-treated active RA which normalized after conventional RA treatment. These findings suggest that RA activity and/or conventional treatment affect the regulation of central secretion of PRL (67). A study was done to evaluate the relation between the level of leptin, PRL, IL-4 and IL-5 with the activity of RA and SLE. The authors concluded that leptin cannot be used to evaluate disease activity in these entities, while PRL can be utilized to assess disease activity in RA and SLE (68). Despite these controversies, PRL receptors were identified in fibroblast-like synovial cells and lymphocytes which infiltrate the synovial membrane. PRL was synthesized by both synovium infiltrating T lymphocytes and fibroblast-like synovial cells. PRL increases synovial proliferation and the production of pro-inflammatory cytokines and

metalloproteases. Bromocriptine (BRC) reduces not only PRL production, but proinflammatory cytokines and collagenases by RA synovial cells (69). The PRL gene is located in close proximity to the HLA region on the short arm of chromosome 6. It has been proposed the hypothesis that the associations between DR4 and reproductive risk factors in RA are due to linkage unbalance between DR4 and an

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abnormally regulated PRL gene polymorphism (70). In fact, there is a linkage disequilibrium between HLA-DRB1 disease susceptibility alleles, and microsatellite markers close to the PRL gene, among women with RA and SLE (71). In contrast, none of the polymorphisms of neuroendocrine genes, including PRL gene, showed any statistically significant associations with JIA (72). PRL -1149 T (minor) allele decreases PRL expression and may be associated with AD. In order to determine the role of the PRL -1149 G/T polymorphism (rs1341239) in RA susceptibility, the association between PRL -1149 G/T and RA risk was examined in 3,405 RA cases and 4,111 controls. The results of this study indicate a possible association between the PRL -1149 T allele and decreased RA risk (73). In conclusion: There is a growing body of evidence demonstrating an intriguing link between PRL and RA in humans. New studies are necessary in order to recognize the PRL action mechanisms in RA and to prove the efficacy of PRL antagonists in this disease (74). Hormones and Neurotransmitters: A bridge toward the Adaptive Response across the Immune Response

The chromatin structure, either closed or open-permissive in the vicinity of lineagespecific genes, is a determinant regulator of gene expression. Therefore in the framework of adaptive immune response is indispensable. a highly dynamic epigenetic flexibility

through the modification of chromatin structure either to induce or suppress the expression of lineage specific genes. The modification of meH3K9, meH3K27 and other restrictive histone molecules and the suppression of histone deacetylase activity on the closed chromatin structure, leads to the accessibility of transcription factors to lineage specific genes. Conversely, permissive histone may be modified to silence the expression of a gene (75).

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RA affects women more frequently than men (ratio 4:1); its clinical severity is significantly modified by the different stages of the ovarian cycle. It is suppressed by pregnancy and progressive exacerbation starts within two or three weeks after delivery; therefore breast feeding is habitually suppressed once RA treatment is resumed (76). The forkhead-box-p3 (Foxp3) is a lineage-specific transcription factor and the major regulator of the development of CD4+CD25+ natural Treg cells in the thymus. These cells constitute approximately 10% of peripheral TCD4+ cells in normal individuals and are involved in the control of the immune response and regulate tolerance against harmless non-self or self-Ags. Foxp3 expression inhibits the transcription of gene encoding IL-2 and up-regulates the expression of CD25 and other Treg cellassociated molecules. CD25, the interleukin-2 (IL-2) receptor -chain and CD122, the IL-2 receptor chain encoding genes are up-regulated by Foxp3, which is characteristically expressed by CD4+Treg cells (77). STAT5 molecules are key components of the IL-2 signaling to up-regulate Foxp3. STAT5a and STAT5b molecules play important roles in intracellular signal transduction after cellular stimulation by a wide spectrum of cytokines, growth factors and hormones. Naturally occurring Treg (nTreg) cells are generated and maintained in an IL-2-dependent manner, as demonstrated by the development of autoimmune disease in mice deficient for IL-2, IL-2R and IL-2R, that result of a reduced number of natural Treg cells. Additionally, a subset of STAT5a and STAT5b double-knockout mice also develop autoimmune pathology similar to that expressed by IL-2 or IL-2R knockout mice. Therefore, epigenetic changes induced by cytokine gene expression are essential to activate Foxp3 in natural Treg cells, as occurs with other lineage transcription factors: the GATAbinding protein 3 (GATA-3) for Th2 cells, and the retinoic orphan receptor C2 for Th17 cells (78, 79).

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It has been demonstrated that STAT1-activating cytokines IL-27 and IFN- amplify TGF-induced Foxp3 expression in inducible-Treg (iTreg) cells in the periphery (outside the thymus) generated from CD4+CD25- nave T cells and that the coupled stimuli of these cytokines polarizes differentiation to the Treg cell phenotype, with reduced IFN- production and potent suppressive activity (79). Foxp3 bound to NFAT (nuclear factor of activated T cells) and AML1 (acute leukemia-1)/Runx1 (runt-related transcription factor1) interacts as a molecular complex with activator protein1 and nuclear factor kB to induce the repression the IL-2 and other cytokine genes and up-regulate the expression of genes encoding CD25, cytotoxic lymphocyte-associated antigen-4 (CTLA-4), and GITR (glucocorticoid-induced TNF receptor family-related protein); therefore the decreased expression of foxp3 induced by Th1-derived cytokines results in a reduced number of CD4+CD25+ Treg cells and autoimmunity. The permanently changing microenvironment as a result of the presence of cytokines which induce the epigenetic expression of coactivator or corepressor proteins, micro-RNA genes and other transcription factors are crucial factors in the framework where Foxp3 controls hundreds of genes directly or indirectly (80).

The rapid adaptive phenotype changes of the immune response require the expression of specific genes, which are controlled by trans-acting factors. Transcription factors (TFs) and microRNAs (miRNAs) acting in coordination, regulate these processes in different and complementary ways. Additionally, it is speculated that the unique characteristics of miRNAs, including its wide cytoplasm distribution on ribosomes and its restricted and compartmentalized mRNA substrate, allows miRNAs to regulate specialized niches such as the neuronal and immunological synapses (81). Therefore we can imagine that the instructions to choose a specific pathway within

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this intracellular labyrinth are encoded in cards hidden within cryptic spaces whose conformational structure is maintained by padlocked chains that prevent any conformational change except when sequential signals derived from different sources located either in the same or distinct compartments are joined just at the moment that padlock may be opened to obtain the coded card. It is highly probable that ovarian hormones, mainly 17 -estradiol, exert significant control over CTLA-4 activity into pathogenic immunological synapse occurring on the rheumatoid follicle. Differentiation of CD4+CD25high Foxp3+ Tregs is increased in the late follicular phase of the menstrual cycle and a close correlation between serum levels of 17 -estradiol and the number of these cells has been observed,13 although a dramatic decrease in Tregs is observed in the luteal phase in normal fertile women(82, 83). Therefore, it is possible that, in RA patients, increased synthesis of citrullinated peptides induced by estrogen in the follicular phase occurs just before the fall of CD4+CD25highFoxP3+ Tregs in the luteal phase, inducing uncontrolled generation of anticitrullinated peptide antibodies.

Clinical exacerbation of RA is frequently observed one week before menstruation, and it has been suggested that the estrogen peak that precedes ovulation acts as an enhancer of rheumatoid synovitis (40). However, in contrast, it is also suggested that the clinical severity of RA is suppressed by pregnancy in spite of increased plasma levels of 17 estradiol and progesterone. Microchimerism was described in 1996 as the protracted persistence of fetal cells within circulating maternal venous blood by Bianchi, who sorted fetal mononuclear cells carrying CD antigens 3, 4, 5, 19, 23, 34, and 38 using antibodies against them by flow cytometry. The presence of male fetal cells was demonstrated by PCR amplification of

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DNA sequences for the Y chromosome in 13 of 19 pregnant women carrying a male fetus, and in 4 of 13 pregnancies with female fetuses. Therefore, fetal male cells from previous pregnancies had survived within the maternal bloodstream over protracted periods, such as the case of a woman whose last son was born 27 years before (84). Pregnancy suppresses the inflammatory signals of autoimmunity through enhanced expression of genes encoding non inflammatory cytokines induced by placental hormones, progesterone and -estradiol, which increases the differentiation of T lymphocytes to the CD4+CD25highFoxP3+ Tregs phenotype (85). Additionally, it has been demonstrated that maternal cells cross the placenta to reside in fetal lymph nodes, inducing development of CD4+CD25highFoxP3+ Tregs to suppress fetal antimaternal immunity (86). The persistence of maternal Treg cells in lymph nodes of the son has been observed in young adults. Therefore it is possible that a form of antigen-specific tolerance in humans, induced by microchimerism, remains active in regulating immune responses after birth. It is known that fetal Tregs cells residing in the maternal lymph nodes exert potent down-regulation of maternal immunity to fetal alloantigens. Therefore, it is probable that reciprocal maternal Tregs suppresses the fetal immune response against invading maternal

cells during pregnancy.

In pregnant woman, alloreactivity is biased towards a Th2-like response, with greater secretion of IL-4; it is possible that this cytokine acting in coordination with progesterone and 17- estradiol exerts important modifications on the expression of Tregs cells, increasing their number, phenotype and overall activity to suppress Th1 and Th2 responses against paternal alloantigens but not against unrelated alloantigens and PAMP signals (85). It has been demonstrated that human chorionic gonadotropin (hCG) and 17 -

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estradiol (E2) inhibit the T-cell stimulatory capacity of dendritic cells to prevent any allogenic T-cell response against the embryo (87). Additionally, it has been reported that hCG induce potent up-regulation of MIF (macrophage migration inhibitory factor) mRNA expression in endometrial stromal cells. Therefore, MIF may exert an immunomodulatory activity to suppress the expression of inflammatory Th-1 derived cytokines (88). Once pregnancy has been established, a potent up-regulation of progesterone receptors is triggered amongst activated lymphocytes, placental cells and decidual CD56+ cells to increase the synthesis of progesterone induced blocking factor (PIBF). This mediator activates B cells to increase the production of asymmetric non-cytotoxic antibodies and modulates the profile of cytokine secretion by activated lymphocytes increasing the production of non-inflammatory non-cytotoxic interleukins (IL) mainly IL-3, IL-4 and IL-10.

In addition PIBF induces decreased production of inflammatory cytotoxic cytokines such as interferon (IFN)-delta, TNF and IL-2, inducing the suppression of cytokine-induced NK cells transformation and consequently a reduced release of perforin and degranulation molecules; PIBF additionally exerts a substantial anti-abortive activity (89).

CD4+CD25high regulatory T cells are lowered in the second trimester of human pregnancy, but even so these cells display potent suppression of IL-2, TNF- and IFN- secretion from responder cells and a high capacity to increase the synthesis of Il-4 and IL10. It has been speculated that progesterone acts as a master regulator of Tregs cells activity, inducing an altered phenotype consisting of reduced Foxp3 expression, enhanced frequency of CD45R0+ and reduced frequency of CD45RA+, which enables these cells to

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efficiently down-regulate the inflammatory immune response during pregnancy.27Mjsberg Depletion of fetal Tregs (CD25+T cells) results in significantly-increased proliferation of fetal T cells against maternal or autologous APCs, but only a slight increase against unrelated APCs. Therefore, it is highly probable that a large pool of fetal Tregs actively suppress T cell responses against self-antigens and that microchimerism, either maternal or foetal, and clinical silencing of RA results from the over activity of Tregs both in the foetus and in pregnant women (90).

Concluding Remarks

The clinical expression of RA varies widely between individual patients and over time in the same patient. These clinical variations are difficult to explain, but advances in our knowledge of the molecular mechanisms about regulation of interaction of the innate and adaptive immune response provide clues to construct solid concepts on the production of ectopic lymphoid follicles. Similar, the knowledge about the surprisingly-rapid activation of a wide repertoire of signaling pathways that drive the differentiation of a primed T lymphocyte. Then, this T lymphocyte become an self-reactive effector cell that is either, rapidly deleted or becomes a highly specialized long-lived memory cell arising directly from native cells bypassing the effector stage and enable the recognition of foreign antigens and contributing to the coordination of activity with B memory cells and the interaction between APC and T naive cell. Rapid adaptive phenotype changes in the immune response require the expression of specific genes that are controlled by trans-acting factors. Transcription factors (TFs) and micro-RNAs (miRNAs) acting in coordination regulate these processes in different and complementary ways. It is also suggested that the unique characteristics of miRNAs, such

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as the widely cytoplasm distribution on ribosomes and its restricted and compartmentalized mRNA substrate, permit miRNAs to regulate specialized niches such as neuronal and immunolgical synapses. RA results from an immunological synapse that occurs in a tertiary lymphoid follicle in the synovial membrane whose microenvironment has been severely modified by proinflammatory cytokines released by dendritic cells to prime differentiation of ThCD4+ lymphocytes. The suppression of CTLA-4 activity and the enhancement of inflammatory signals induced by the activation of HMGB1 constitute the hallmark of the rheumatoid follicle. However, this highly pathogen inflammatory microenvironment is also highly sensitive to regulatory signals emerging either as hormones from the endocrine system or by neurotransmitters released by the vegetative nervous system. This is clearly evidenced by the silencing of RA induced by pregnancy.

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