Concept: Systemic autoimmune diseases
Rheumatoid arthritis (RA) is a systemic autoimmune disease, caused by both genetic and environmental factors. Recently, investigators have focused on the gut microbiota, which is thought to be an environmental agent affecting the development of RA. Here we review the evidence from animal and human studies that supports the role of the gut microbiota in RA. We and others have demonstrated that the abundance of Prevotella copri is increased in some early RA. We have also used gnotobiotic experiments to show that dysbiosis in RA patients contributed to the development of Th17 cell-dependent arthritis in intestinal microbiota-humanized SKG mice. On the other hand, Prevotella histicola from human gut microbiota suppressed the development of arthritis. In summary, Prevotella species are involved in the pathogenesis of arthritis.
Dogs can spontaneously develop complex systemic autoimmune disorders, with similarities to human autoimmune disease. Autoantibodies directed at self-antigens are a key feature of these autoimmune diseases. Here we report the identification of interleukin enhancer-binding factors 2 and 3 (ILF2 and ILF3) as autoantigens in canine immune-mediated rheumatic disease. The ILF2 autoantibodies were discovered in a small, selected canine cohort through the use of human protein arrays; a method not previously described in dogs. Subsequently, ILF3 autoantibodies were also identified in the same cohort. The results were validated with an independent method in a larger cohort of dogs. ILF2 and ILF3 autoantibodies were found exclusively, and at a high frequency, in dogs that showed a speckled pattern of antinuclear antibodies on immunofluorescence. ILF2 and ILF3 autoantibodies were also found at low frequency in human patients with SLE and Sjögren’s syndrome. These autoantibodies have the potential to be used as diagnostic biomarkers for canine, and possibly also human, autoimmune disease.
Autoimmune rheumatic diseases pose many problems that have, in general, already been solved in the field of cancer. The heterogeneity of each disease, the clinical similarities and differences between different autoimmune rheumatic diseases and the large number of patients that remain without a diagnosis underline the need to reclassify these diseases via new approaches. Knowledge about the molecular basis of systemic autoimmune diseases, along with the availability of bioinformatics tools capable of handling and integrating large volumes of various types of molecular data at once, offer the possibility of reclassifying these diseases. A new taxonomy could lead to the discovery of new biomarkers for patient stratification and prognosis. Most importantly, this taxonomy might enable important changes in clinical trial design to reach the expected outcomes or the design of molecularly targeted therapies. In this Review, we discuss the basis for a new molecular taxonomy for autoimmune rheumatic diseases. We highlight the evidence surrounding the idea that these diseases share molecular features related to their pathogenesis and development and discuss previous attempts to classify these diseases. We evaluate the tools available to analyse and combine different types of molecular data. Finally, we introduce PRECISESADS, a project aimed at reclassifying the systemic autoimmune diseases.
For many years primary Sjögren’s syndrome (pSS) has been considered an orphan disease, since no specific therapies were recognized as being capable of contrasting the development and progression of this disorder. The treatment of oral and ocular features, as well as of the systemic organ involvement, has been entrusted to the joint management of different subspecialty physicians, like ophthalmologists, otolaryngologists, dentists and rheumatologists. These latter subspecialty doctors are usually more involved in the treatment of systemic extraglandular involvement and, to do it, they have long been using the conventional therapies borrowed by the treatment schedules adopted in other systemic autoimmune diseases. The increasing knowledge of the biological pathways that are operative in patients with pSS, and the parallel development of molecular biology technology, have allowed the production and availability of a number of biological agents able to positively act on different disease mechanisms, and thus are candidates for testing in therapeutic trials. Meanwhile, the scientific community has made a great effort to develop new accurate and validated classification criteria and outcome measures to be applied in the selection of patients to be included and monitored in therapeutic studies. Some of the new-generation biotechnological agents have been tested in a number of open-label and randomized controlled trials that have produced in many cases inconclusive or contradictory results. Behind the differences in trial protocols, adopted outcome measures and predefined endpoints, reasons for such unsatisfactory results can be found in the large heterogeneity of clinical subtypes in the examined cohorts. The future challenge for a substantial advancement in the therapeutic approach to pSS could be to identify the pathologic mechanisms, outcome tools and biomarkers that characterize the different subsets of the disease in order to test carefully selected target therapies with the highest probability of success in each different clinical phenotype.
Autoimmune sensorineural hearing loss, also known as autoimmune inner ear disease (AIED) is a rare clinical entity characterized by progressive and bilateral sensorineural hearing loss often accompanied by vestibular symptoms. Diagnosis is essential as a consistent number of patients show a positive response to steroids alone or in association with other immunosuppressive drugs. AIED is defined as primary when the disease is limited to the ear, whereas in up to a third of cases it is associated to other systemic autoimmune diseases such as Behçet disease (BD). BD is a rare multisystem vasculitis characterized by recurrent oral and genital aphtosis, uveitis, skin lesions, neurological and vascular manifestations. Clinical presentation is variable thus making the diagnosis difficult in many instances. The choice of therapy is also limited by the scarceness of high-quality therapy studies.
Effects of hydroxychloroquine on symptomatic improvement in primary Sjögren syndrome: the JOQUER randomized clinical trial
- JAMA : the journal of the American Medical Association
- Published over 4 years ago
Primary Sjögren syndrome is a systemic autoimmune disease characterized by mouth and eye dryness, pain, and fatigue. Hydroxychloroquine is the most frequently prescribed immunosuppressant for the syndrome. However, evidence regarding its efficacy is limited.
- European journal of endocrinology / European Federation of Endocrine Societies
- Published over 3 years ago
The physiological persistence of fetal cells in the circulation and tissues of a previously-pregnant woman is called fetal cell microchimerism (FCM). It was hypothesized to play a role in systemic autoimmune diseases, but in autoimmune thyroid disease (AITD) only limited data are available.
Crying Without Tears: Dimensions of Crying and Relations With Ocular Dryness and Mental Well-Being in Patients With Sjögren’s Syndrome
- Journal of clinical psychology in medical settings
- Published over 3 years ago
This study examined dimensions of crying and its relations with ocular dryness and mental well-being in patients with Sjögren’s syndrome, a systemic autoimmune disease with dryness as primary symptom. Three-hundred patients with Sjögren’s syndrome completed questionnaires on crying, dryness, and well-being. The crying questionnaire revealed four dimensions: “Cryability” (comprising both crying sensibility and ability to cry), Somatic consequences, Frustration, and Suppression. Compared to 100 demographically-matched control participants from the general population, patients scored low on Cryability and high on Somatic consequences and Frustration. The crying dimensions generally showed significant but weak associations with ocular dryness and mental well-being in patients. This is the first quantitative study indicating that crying problems are more common in patients with Sjögren’s syndrome than in the general population. Perhaps, patients who experience problems with crying could be helped to rely on other ways of expressing emotions than crying in tear-inducing situations.
Rheumatoid arthritis (RA) is a systemic autoimmune disease manifesting in joint destruction. The recognized hallmark of RA pathogenesis is the involvement of immune cells which produce many mediators potentiating an inflammatory environment. RA synovial fibroblasts (RASFs) contribute significantly to disease progression by initiating and regulating many pathways of joint destruction. Detailed molecular insights into RASF biology may lead to identification of important therapeutic targets. The discovery of common molecular targets for joint resident and inflammatory cells may help to develop the most effective therapeutic strategy. One such pathway includes semaphorin 4A as reported in a recent article in Arthritis Research & Therapy.
Patients with systemic autoimmune diseases show increased incidence of atherosclerosis. However, the contribution of proatherogenic factors to autoimmunity remains unclear. We found that atherogenic mice (herein referred to as LDb mice) exhibited increased serum interleukin-17, which was associated with increased numbers of T helper 17 (Th17) cells in secondary lymphoid organs. The environment within LDb mice was substantially favorable for Th17 cell polarization of autoreactive T cells during homeostatic proliferation, which was considerably inhibited by antibodies directed against oxidized low-density lipoprotein (oxLDL). Moreover, the uptake of oxLDL induced dendritic-cell-mediated Th17 cell polarization by triggering IL-6 production in a process dependent on TLR4, CD36, and MyD88. Furthermore, self-reactive CD4(+) T cells that expanded in the presence of oxLDL induced more profound experimental autoimmune encephalomyelitis. These findings demonstrate that proatherogenic factors promote the polarization and inflammatory function of autoimmune Th17 cells, which could be critical for the pathogenesis of atherosclerosis and other related autoimmune diseases.