Dendritic cells drive profibrotic inflammation and aberrant T cell polarization in systemic sclerosis.

OBJECTIVES: SSc is a devastating autoimmune disease characterized by fibrosis and obliterative vasculopathy affecting the skin and visceral organs. While the processes mediating excessive extracellular matrix deposition and fibroblast proliferation are clear, the exact link between autoimmunity and fibrosis remains elusive. Th17 cells have been proposed as critical drivers of profibrotic inflammation during SSc, but little is known about the immune components supporting their pathogenic role. Our aim was to determine cytokine responses of stimulated monocyte-derived dendritic cells (Mo-DCs) and to determine how they influence T-cell cytokine production in SSc. MATERIAL AND METHODS: Dendritic cells (DCs) activate and shape T cell differentiation by producing polarizing cytokines. Hence, we investigated the cytokine responses of monocyte-derived DCs (Mo-DCs) from patients with limited cutaneous SSc (lcSSc), diffuse cutaneous SSc (dcSSc) and healthy controls (HCs) after stimulation with toll-like receptor (TLR) agonists. Also, using co-culture assays, we analysed T cell subpopulations after contact with autologous TLR-activated Mo-DCs. RESULTS: In general, we observed an increased production of Th17-related cytokines like IL-1ß, IL-17F, IL-21 and IL-22 by SSc compared with HC Mo-DCs, with variations between lcSSc vs dcSSc and early- vs late-stage subgroups. Noticeably, we found a significant increment in IL-33 production by Mo-DCs in all SSc cases regardless of their clinical phenotype. Strikingly, T cells displayed Th2, Th17 and dual Th2-Th17 phenotypes after exposure to autologous TLR-stimulated Mo-DCs from SSc patients but not HCs. These changes were pronounced in individuals with early-stage dcSSc and less significant in the late-stage lcSSc subgroup. CONCLUSIONS: Our findings suggest that functional alterations of DCs promote immune mechanisms favouring the aberrant T cell polarization and profibrotic inflammation behind clinical SSc heterogeneity.

Differential Leukocyte Expression of IFITM1 and IFITM3 in Patients with Severe Pandemic Influenza A(H1N1) and COVID-19.

Interferon-induced transmembrane (IFITM) proteins mediate protection against enveloped viruses by blocking membrane fusion at endosomes. IFITM1 and IFITM3 are crucial for protection against influenza, and various single nucleotide polymorphisms altering their function have been linked to disease susceptibility. However, bulk IFITM1 and IFITM3 mRNA expression dynamics and their correlation with clinical outcomes have not been extensively addressed in patients with respiratory infections. In this study, we evaluated the expression of IFITM1 and IFITM3 in peripheral leukocytes from healthy controls and individuals with severe pandemic influenza A(H1N1) or coronavirus disease 2019 (COVID-19). Comparisons between participants grouped according to their clinical characteristics, underlying disease, and outcomes showed that the downregulation of IFITM1 was a distinctive characteristic of severe pandemic influenza A(H1N1) that correlated with outcomes, including mortality. Conversely, increased IFITM3 expression was a common feature of severe pandemic influenza A(H1N1) and COVID-19. Using a high-dose murine model of infection, we confirmed not only the downregulation of IFITM1 but also of IFITM3 in the lungs of mice with severe influenza, as opposed to humans. Analyses in the comparative cohort also indicate the possible participation of IFITM3 in COVID-19. Our results add to the evidence supporting a protective function of IFITM proteins against viral respiratory infections in humans.

Possible Role of Matrix Metalloproteinases and TGF-ß in COVID-19 Severity and Sequelae.

The costs of coronavirus disease 2019 (COVID-19) are devastating. With millions of deaths worldwide, specific serological biomarkers, antiviral agents, and novel therapies are urgently required to reduce the disease burden. For these purposes, a profound understanding of the pathobiology of COVID-19 is mandatory. Notably, the study of immunity against other respiratory infections has generated reference knowledge to comprehend the paradox of the COVID-19 pathogenesis. Past studies point to a complex interplay between cytokines and other factors mediating wound healing and extracellular matrix (ECM) remodeling that results in exacerbated inflammation, tissue injury, severe manifestations, and a sequela of respiratory infections. This review provides an overview of the immunological process elicited after severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Also, we analyzed available data about the participation of matrix metalloproteinases (MMPs) and transforming growth factor-beta (TGF-ß) in immune responses of the lungs. Furthermore, we discuss their possible implications in severe COVID-19 and sequela, including pulmonary fibrosis, and remark on the potential of these molecules as biomarkers for diagnosis, prognosis, and treatment of convalescent COVID-19 patients. Our review provides a theoretical framework for future research aimed to discover molecular hallmarks that, combined with clinical features, could serve as therapeutic targets and reliable biomarkers of the different clinical forms of COVID-19, including convalescence.

Clinical and Immunological Factors That Distinguish COVID-19 From Pandemic Influenza A(H1N1).

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is a global health threat with the potential to cause severe disease manifestations in the lungs. Although COVID-19 has been extensively characterized clinically, the factors distinguishing SARS-CoV-2 from other respiratory viruses are unknown. Here, we compared the clinical, histopathological, and immunological characteristics of patients with COVID-19 and pandemic influenza A(H1N1). We observed a higher frequency of respiratory symptoms, increased tissue injury markers, and a histological pattern of alveolar pneumonia in pandemic influenza A(H1N1) patients. Conversely, dry cough, gastrointestinal symptoms and interstitial lung pathology were observed in COVID-19 cases. Pandemic influenza A(H1N1) was characterized by higher levels of IL-1RA, TNF-α, CCL3, G-CSF, APRIL, sTNF-R1, sTNF-R2, sCD30, and sCD163. Meanwhile, COVID-19 displayed an immune profile distinguished by increased Th1 (IL-12, IFN-γ) and Th2 (IL-4, IL-5, IL-10, IL-13) cytokine levels, along with IL-1ß, IL-6, CCL11, VEGF, TWEAK, TSLP, MMP-1, and MMP-3. Our data suggest that SARS-CoV-2 induces a dysbalanced polyfunctional inflammatory response that is different from the immune response against pandemic influenza A(H1N1). Furthermore, we demonstrated the diagnostic potential of some clinical and immune factors to differentiate both diseases. These findings might be relevant for the ongoing and future influenza seasons in the Northern Hemisphere, which are historically unique due to their convergence with the COVID-19 pandemic.

Corrigendum: CXCL17 Is a Specific Diagnostic Biomarker for Severe Pandemic Influenza A(H1N1) That Predicts Poor Clinical Outcome.

[This corrects the article DOI: 10.3389/fimmu.2021.633297.].

Expression of Surfactant Protein D Distinguishes Severe Pandemic Influenza A(H1N1) from Coronavirus Disease 2019.

The differentiation between influenza and coronavirus disease 2019 (COVID-19) could constitute a diagnostic challenge during the ongoing winter owing to their clinical similitude. Thus, novel biomarkers are required to enable making this distinction. Here, we evaluated whether the surfactant protein D (SP-D), a collectin produced at the alveolar epithelium with known immune properties, was useful to differentiate pandemic influenza A(H1N1) from COVID-19 in critically ill patients. Our results revealed high serum SP-D levels in patients with severe pandemic influenza but not those with COVID-19. This finding was validated in a separate cohort of mechanically ventilated patients with COVID-19 who also showed low plasma SP-D levels. However, plasma SP-D levels did not distinguish seasonal influenza from COVID-19 in mild-to-moderate disease. Finally, we found that high serum SP-D levels were associated with death and renal failure among severe pandemic influenza cases. Thus, our studies have identified SP-D as a unique biomarker expressed during severe pandemic influenza but not COVID-19.

Aspartic acid70 in the HLA-DRB1 chain and shared epitope alleles partially explain the high prevalence of autoimmunity in Mexicans.

INTRODUCTION: Autoimmune thyroid disease (AITD) is the most common autoimmune disorder worldwide. Remarkably, it is commonly accompanied by other autoimmune diseases, such as rheumatoid arthritis (RA). The immunopathogenic mechanisms behind the coexistence of these disorders are still not completely understood. Immunogenetics influences the physiopathology of these diseases since ethnicity plays an essential role in the inheritance of susceptibility markers. METHODS: High-resolution HLA class II typing was performed using a sequence-based method. RESULTS: The allele frequency of HLA-DRB1∗04:04 and -DRB1∗03:01 were significantly increased in patients with AITD and RA compared to healthy individuals, pC â€‹= â€‹0.021, OR â€‹= â€‹2.4, 95%CI â€‹= â€‹1.19-4.75 and pC â€‹= â€‹0.009, OR â€‹= â€‹3.4, 95%CI â€‹= â€‹1.42-7.93, respectively. Remarkably, these patients have a combined risk given by susceptibility HLA-DRB1 alleles that contain the shared epitope, pC â€‹= â€‹0.03, OR â€‹= â€‹1.7, IC95% â€‹= â€‹1.07-2.76, and a lack of protective alleles carrying aspartic acid70, pC â€‹= â€‹0.009, OR â€‹= â€‹0.5, IC95% â€‹= â€‹0.32-0.84. DISCUSSION: The results suggest that patients with AITD and RA have an immunogenetic mechanism that combines the susceptibility alleles associated with both diseases. Importantly, it seems to be linked mainly to the lack of protective alleles with aspartic acid in the position 70, along with the presence of susceptibility alleles that have the sequences QRRAA, QKRAA, and RRRAA at positions 70-74. CONCLUSION: Patients with AITD and RA have a characteristic immunogenetic signature, which could be useful for determining multiple autoimmunities and assessing their relatives' risk of developing it.

Pan-American League of Associations for Rheumatology (PANLAR) capillaroscopy study group consensus for the format and content of the report in capillaroscopy in rheumatology.

OBJECTIVE: The aim of this work was to produce a consensus-based report for capillaroscopy in rheumatology to be used in daily clinical practice. METHODS: A written Delphi questionnaire regarding capillaroscopy report was developed from a literature review and expert consensus. The Delphi questionnaire was sent to an international panel including 25 rheumatologists experts in capillaroscopy, asking them to rate their level of agreement or disagreement with each statement. The exercise consisted of three online rounds and a face-to-face (live meeting) that took place in the PANLAR 2018 congress held in Buenos Aires, Argentina. RESULTS: The participants to the first, second, third, and face-to-face round were 22, 21, 21, and 16 rheumatologists, respectively. Fifty-five items were discussed in the first round, 58 in the second, 22 in the third, and 9 in the face-to-face meeting. At the end of the exercise, 46 recommendations for the capillaroscopy report in rheumatology reached a consensus. CONCLUSION: This is the first consensus-based report in capillaroscopy. It will be useful in daily clinical practice and to address the effort of the standardization in the technique. KEY POINTS: • The current lack of consensus for the capillaroscopy report makes difficult the interpretation of findings as well as follow-up of rheumatic diseases. • This study produced the first international consensus for the format and content of the naifold capillaroscopy report in rheumatology. • The report is an integral part of the capillaroscopy examination and its use in a homogeneous form can help in the correct interpretation of findings in daily practice.

Can nailfold videocapillaroscopy images be interpreted reliably by different observers? Results of an inter-reader and intra-reader exercise among rheumatologists with different experience in this field.

Nailfold videocapillaroscopy (VCP) allows non-invasive assessment of the microcirculation. Adequate training in this field is relevant for rheumatologists. There is increasing evidence of the reliability of VCP findings among different readers. Objective: To evaluate inter- and intra-reader agreement of rheumatologists to identify normal images and systemic sclerosis (SSc) patterns on VCP ("early," "active," and "late" proposed by Cutolo et al.). Thirteen rheumatologists with different experience in nailfold VCP received training to standardize reading criteria. They rated 60 VCP images from healthy and SSc patients at baseline and 4 weeks later, using an electronic platform. The reading of an expert was considered the gold standard. Data were analyzed using Cohen's kappa for concordance and Student's t test and ANOVA to compare kappa means for inter-reader, intra-reader, and inter-pattern readings. Mean inter-reader and intra-reader kappa were 0.45 and 0.49, respectively, (moderate agreement). Kappa scores were higher among experienced vs inexperienced readers (inter-reader kappa 0.58 vs 0.34, p = 0.001, intra-reader kappa 0.65 vs 0.37, p = 0.01). Agreement was substantial (kappa = 0.61) for the identification of normal vs abnormal images and higher for the identification of active (0.48, p = 0.009) and late SSc patterns (0.56, p = 0.008) than for the early SSc pattern (0.35, p = 0.003). There is moderate agreement among rheumatologists for the identification of SSc videocapillaroscopy patterns (higher among experienced rheumatologists) and substantial agreement, regardless of previous experience in VCP, in the identification of normal and abnormal images. Agreement for the identification of active and late patterns is higher than for the early pattern.

Pulmonary Vasoreactivity and Phenotypes in Pulmonary Arterial Hypertension Associated to Connective Tissue Diseases.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a fatal complication in patients with connective tissue disease (CTD). OBJECTIVE: The objective of the study was to study the prognostic value of the acute pulmonary vasoreactivity test with inhaled iloprost and its association with clinical deterioration in a tertiary care academic medical center. METHODS: We conducted a prospective study of patients with CTD and the diagnosis of PAH established by right heart catheterization. Patients were classified into classic responders, partial responders, and non-responders. The association of the pulmonary response and clinical deterioration was analyzed. RESULTS: We enrolled 25 patients (mean age of 47 ± 13.4 years); 88% were female. The most frequent rheumatologic diagnosis was systemic lupus erythematosus, in 16 (64%) patients. Seventy-two percent of patients were classified as non-responders, and 28% were partial responders. Patients with a partial response had lower right atrial pressure values (5.1 ± 3.1 vs. 8.5 ± 3.2, p = 0.01) and greater systolic pulmonary arterial pressure (87.6 ± 8.1 vs. 72.4 ± 16.2, p = 0.02), compared with non-responders. Non-responders had a tendency for a shorter time to clinical deterioration than partial responders (17.8 vs. 41.1 months, p = 0.052). CONCLUSIONS: Patients with a partial response to the acute pulmonary vasodilator test with inhaled iloprost had a longer clinical deterioration-free period than non-responders.

Practice guidelines for the management of low back pain. Consensus Group of Practice Parameters to Manage Low Back Pain.

It has been documented that pain in its diverse modalities is the most common cause of medical attention. In Mexico, an increase in its frequency has promoted its consideration in several health programs. On the other hand, inadequate pain management will cause severe physical, psychoaffective, and socioeconomic repercussions for patients, families, and public health services. Despite this panorama, there has not been an agreement to establish better diagnostic and therapeutic methods for the management of chronic pain. A consensus group was reunited and was integrated by medical experts from private and public institutions and from various states of the Mexican Republic. To assure the development of these practice guidelines, these experts had experience in the assessment and treatment of conditions causing pain. With the guidelines used by other consensus groups, meetings were held to analyze and discuss published literary evidence for the management of low back pain. The recommendations were classified according to their methodological strength. As a result of this meeting, consensus recommendations were based on evidence and operational conclusions of such proactive educational plans, institutional policies and diagnostic recommendations for pharmacological and nonpharmacological treatment in order for Mexican physicians to provide a better therapeutic approach to low back pain.

Rheumatic manifestations of inflammatory bowel disease.

This article reviews the literature concerning rheumatic manifestations of inflammatory bowel disease (IBD), including common immune-mediated pathways, frequency, clinical course and therapy. Musculoskeletal complications are frequent and well-recognized manifestations in IBD, and affect up to 33% of patients with IBD. The strong link between the bowel and the osteo-articular system is suggested by many clinical and experimental observations, notably in HLA-B27 transgenic rats. The autoimmune pathogenic mechanisms shared by IBD and spondyloarthropathies include genetic susceptibility to abnormal antigen presentation, aberrant recognition of self, the presence of autoantibodies against specific antigens shared by the colon and other extra-colonic tissues, and increased intestinal permeability. The response against microorganisms may have an important role through molecular mimicry and other mechanisms. Rheumatic manifestations of IBD have been divided into peripheral arthritis, and axial involvement, including sacroiliitis, with or without spondylitis, similar to idiopathic ankylosing spondylitis. Other periarticular features can occur, including enthesopathy, tendonitis, clubbing, periostitis, and granulomatous lesions of joints and bones. Osteoporosis and osteomalacia secondary to IBD and iatrogenic complications can also occur. The management of the rheumatic manifestations of IBD consists of physical therapy in combination with local injection of corticosteroids and nonsteroidal anti-inflammatory drugs; caution is in order however, because of their possible harmful effects on intestinal integrity, permeability, and even on gut inflammation. Sulfasalazine, methotrexate, azathioprine, cyclosporine and leflunomide should be used for selected indications. In some cases, tumor necrosis factor-alpha blocking agents should be considered as first-line therapy.

The different faces of shared autoimmunity.

The concept of shared autoimmunity comprises various forms of disease: rheumatic diseases in several members of the same family, the coincidence of autoimmune rheumatic with non-rheumatic diseases in relatives of patients, the presence of autoantibodies in healthy relatives of autoimmune disease patients, and the development of two or more autoimmune rheumatic diseases in one patient, the so-called overlap syndromes. The genetic and environmental factors that lead to these phenomena interact in a complex fashion and influence the distinct phenotypic characteristics of each patient. In a previous case series, we described 23 Mexican Mestizo patients with overlap syndromes. Interestingly, rhupus tends to develop sequentially while sclerodermatomyositis tends to appear simultaneously. The clinical course of the other overlap syndromes is rather aggressive, although clinical manifestations respond to standard treatment. The second and/or third disease appears while the first one is still active, even with adequate treatment. The distinct course of overlap syndromes may be partially explained by the interplay of environmental factors with genes that predispose to autoimmunity in general and to manifestations of specific diseases. The analyses of genes that will help understand the pathophysiology of these diseases include several MHC complex genes, cytokines, AIRE, and PDCD1 amongst others.

Overlap syndromes in the context of shared autoimmunity.

The presence of autoimmune rheumatic diseases in several members of the same family, the concurrence of autoimmune rheumatic with non-rheumatic diseases in relatives of patients, the presence of autoantibodies in sera from healthy relatives of autoimmune-disease patients, the development of two or more autoimmune rheumatic diseases in one patient and the interplay of genetic and environmental factors leading to the presence of several autoimmune disease and/or their autoantibodies in families, is being termed "shared autoimmunity". Herein we analyzed autoimmune rheumatic overlap syndromes in this context. We performed a retrospective analysis of the clinical, serological and radiological characteristics of patients with overlap syndromes from the Clinic of Rheumatic Diseases at the Department of Immunology and Rheumatology of the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. We found 23 patients with overlap syndromes; 13 patients with rhupus, 5 with sclerodermatomyositis, 3 with scleroderma and SLE, one with sclerodermatomyositis and SLE and one with scleroderma and MPA. Rhupus tends to develop sequentially while sclerodermatomyositis tends to appear simultaneously. The other overlap syndromes are less common and their clinical course is rather aggressive, although clinical manifestations respond to standard treatment. The second and/or third disease appears while the first one is still active, even with adequate treatment. The coexistence of autoimmune rheumatic diseases may be partially explained by the interplay of environmental factors with genes that predispose to autoimmunity in general and to manifestations of specific diseases. This is part of the concept of Shared Autoimmunity.

Angiotensin II, cell proliferation and angiogenesis regulator: biologic and therapeutic implications in cancer.

Angiotensin II (ANG II) is the main effector peptide in the renin-angiotensin system. It is generated by the activation of Angiotensin I through the Angiotensin II Converter Enzyme (ACE II). ANG II has multiple physiologic effects that regulate vascular tone, hormone secretion, tissue growth and neural activity. It has systemic (endocrine) and local (paracrine and autocrine) effects, favoring cell growth and differentiation through four types of receptors from which types 1 and 2 (AT(1) and AT(2)) are the most important. Stimulation of AT(1) leads to the activation of intracellular pathways that finally lead to vasoconstriction, inflammation and proliferation. The AT(2) receptor is mainly expressed in fetal tissue and scantly in the cardiovascular system under different circumstances. Its effects are opposite to those of the AT(1). The stimulation of AT(1) activates second messengers that lead to a rapid production of diacylglycerol and 1-4-5-inositol triphosphate, as well as to the activation of C protein. Several reports indicate that ANG II can induce neovascularization in experimental systems due to the expression of different growth factors such as angiopoietin 2, vascular endothelial factor, and its receptor, fibroblast growth factor, platelet derived growth factor, transforming growth factor beta and epidermal growth factor. Other mechanisms associated with ANG II induced angiogenesis are nitric oxide synthase and metalloproteinase expression, as well as inflammation induction. Angiogenesis is a fundamental process to tissue repair and development, and it participates in several pathologic processes. In addition, the AT(1) receptor is expressed in many malignant neoplasms and its blockade through ECA II inhibitors and ANG II antagonists has shown antineoplastic activity as well as angiogenesis inhibition in tumoral experimental models. This review discusses the mechanisms by which ANG II participates in neoplastic and non-neoplastic tissue angiogenesis and its possible therapeutic implications.

HLA study on two Mexican Mestizo families with autoimmune thyroid disease.

Several studies have been done regarding the genetic susceptibility to autoimmune thyroid disease, particularly those related to the role of Major Histocompatibility Complex (MHC) genes in the etiology of the disease. In the present study, we report class I and class II MHC haplotypes in nine individuals affected by Hashimoto thyroiditis and Graves' disease who belong to two distinct Mexican families. In one of the families, Hashimoto thyroiditis was associated with the Human Leukocyte Antigen (HLA) HLA-DR3 allele whereas in the other family the disease was associated with homozygosity for the HLA-DR4 (DRB1*0407), HLA-DQ3 (DQB1*0302) haplotype. On the other hand, Graves' disease was found to be associated in one of the families with HLA-DR2 (DRB1*1501) and in the other with homozygosity for the HLA-DR7 (DRB*0701) and HLA-DQ2 (DQB1*0201) haplotype. These results confirm that in Mexicans as in other ethnic groups, genes located within the MHC region are related to the genetic susceptibility to develop autoimmune thyroid disease.