Biological changes in human B-cell line Ramos (RA.1) related to increasing doses of human parathyroid hormone.

Background: The etiopathogenesis of autoimmune diseases is multifactorial, including hormonal factors. Remission of autoimmunity has been observed following treatment for concomitant hyperparathyroidism. Additionally, patients with autoimmune diseases have shown increased expression of parathyroid hormone receptor (PTH1R) and altered distribution of B cells subsets. Hence, this study aims to evaluate potential mechanisms and in vitro effects of PTH stimulation on B lymphocytes. Methods: Using the human B-cell line Ramos (RA.1), various biological effects were evaluated with and without parathyroid hormone (PTH) stimulation at varying concentrations. Flow cytometry was employed to evaluate the phenotype of B lymphocytes based on IgD and CD38 expression, apoptosis induction via Annexin V and proliferation using CFSE. IgM production was quantified through ELISA, and Western blot analysis was performed to assess syk protein phosphorylation as an indicator of cell activation. Results: Ramos cells (RA.1) evidenced a statistically significant change in the phenotype under human PTH stimulation, demonstrating an increased proportion of germinal centre cells (Bm3-Bm4) when stimulated with high concentrations of PTH. Conclusions: The in vitro effects of PTH in B cells subsets align with previous findings of an altered phenotype in B lymphocytes expressing PTH1R among autoimmune disease patients, suggesting a potential role of this hormone in the pathophysiology of autoimmune diseases. However, further studies are necessary to elucidate the mechanisms by which PTH generates observed effects in B lymphocytes and to determine if PTH plays a role in autoimmunity.

Persistent and fatal severe acute respiratory syndrome coronavirus 2 infection in a patient with severe hypogammaglobulinemia: a case report.

BACKGROUND: Viruses are constantly changing as a result of mutations, and new viral variants are expected to appear over time. The virus that causes coronavirus disease 2019, severe acute respiratory syndrome coronavirus 2, is not excluded from this condition. Patients with some types of immunodeficiency have been reported to experience symptoms that vary from mild to severe, or even death, after being infected with severe acute respiratory syndrome coronavirus 2. We report a case of a woman with severe hypogammaglobulinemia who developed a prolonged and fatal severe acute respiratory syndrome coronavirus 2 infection. CASE PRESENTATION: A 60-year-old mestizo female with a previous history of severe hypogammaglobulinemia manifested by recurrent pulmonary infections and follicular bronchiolitis. She received a monthly treatment of intravenous immunoglobulins and was admitted after report of a neurological manifestation related to a left thalamic inflammatory lesion, for a duration of 2 weeks of hospitalization, indicated for the study of her neurological condition, including brain biopsy. Both on admission and 1 week later, nasopharyngeal polymerase chain reaction tests for severe acute respiratory syndrome coronavirus 2 were performed and reported negative. In the third week of hospitalization, she developed pulmonary symptoms, and a positive test result for severe acute respiratory syndrome coronavirus 2 was evidenced. On Day 3, the patients' condition worsened as the infection progressed to respiratory failure and required mechanical ventilation. On Day 8 after the coronavirus disease 2019 diagnosis, the polymerase chain reaction test for severe acute respiratory syndrome coronavirus 2 showed persistent detection of the virus. Various bacterial coinfections, including Klebsiella pneumoniae and Enterobacter cloacae, were diagnosed and treated. On Day 35, her pulmonary symptoms worsened, and the results of the severe acute respiratory syndrome coronavirus 2 polymerase chain reaction test remained positive. On Day 36, despite all the respiratory support, the patient died. The severe acute respiratory syndrome coronavirus 2 virus was sequenced at the beginning and 8 days after the onset of the disease, and the strain, without obvious mutations in the gene that encodes spike protein, was identified. CONCLUSIONS: This clinical case showed persistent severe acute respiratory syndrome coronavirus 2 detection after 35 days of infection in a patient with severe hypogammaglobulinemia. The sequencing of the virus showed no mutations on the spike protein at 8 days, indicating that, in this case, the persistence of the viral detection was associated with immunodeficiency instead of changes in the viral components.

Idiopathic gigantomastia exacerbated during pregnancy. Its relationship with autoimmunity: A case report.

Gigantomastia is a rare entity characterized by diffuse and excessive breast enlargement. It mainly occurs during puberty and pregnancy as a consequence of hormonal fluctuations. We report an unusual case of gigantomastia in a 29-year-old woman with a history of personal and familiar autoimmune phenomena. She had autoimmune thyroiditis and several positive autoantibodies, and developed 3 crises of the disease, 1 related to pregnancy (possibly hormone-mediated), and 2 unrelated to pregnancy in which an autoimmune role is raised based in clinical, histological and laboratory findings. Immunological aspects that may be involved in this presentation of the disease are discussed.

Diagnostic Performance of Anti-dsDNA Tests by Indirect Immunofluorescence and Enzyme-linked Immunosorbent Assay in Patients with Systemic Lupus Erythematosus.

BACKGROUND: Several laboratory techniques for anti double-stranded (ds) DNA detection in systemic lupus erythematosus (SLE) are available, with variable diagnostic performance. We aimed to evaluate anti-dsDNA's diagnostic performance by indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assay (EIA). METHODS: We conducted a single-center retrospective (2015 to 2020) study. Patients with anti-dsDNA tests by IIF and EIA were included. We evaluated the indications, applications, concordance, positive predictive value (PPV) of anti-dsDNA to confirm SLE diagnosis or flares, and associations of disease manifestations with positivity with each technique. RESULTS: A total of 1368 reports of anti-dsDNA tests by IIF and EIA and the corresponding medical records of the patients were analyzed. The main indication for anti-dsDNA testing was to help in the diagnosis of SLE in 890 (65%) of the samples, and the main application after obtaining the results was SLE exclusion in 782 (57.2%) cases. The combination with the highest frequency was the negativity result by both techniques in 801 (58.5%) cases (Cohen kappa 0.57). Both methods were positive in 300 patients with SLE (Cohen kappa 0.42). The PPVs of anti-dsDNA tests to confirm diagnosis/flare was 79.64% (95% CI, 75.35-83.35) by EIA, 78.75% (95% CI, 74.27-82.62) by IIF, and 82% (95% CI, 77.26-85.93) when both were positive. CONCLUSIONS: Anti-dsDNA detection by IIF and EIA are complementary and may indicate different clinical patterns in patients with SLE. The detection of anti-dsDNA antibodies by both techniques has a higher PPV than either separately for confirming SLE diagnosis or flares. These results highlight the need for evaluating both methods in clinical practice.

Circulating and skin biopsy-present cytokines related to the pathogenesis of cutaneous lupus erythematosus.

Cutaneous lupus erythematosus (CLE) is a common disease that may appear as a separate entity from systemic lupus erythematosus (SLE), precede SLE development, or occur as a manifestation of this systemic disease. It has a complex pathophysiology that involves genetic, environmental, and immune-mediated factors creating a self-amplification pro-inflammatory cycle. CLE is characterized by prominent type I interferons (IFNs) inflammation which are considered as the first precursors of the inflammatory cascade generated within the pathophysiology of CLE. TNF-α enhances the production of antibodies through the activation of B cells, and favors the expression of surface nuclear antigens on keratinocytes. UV light exposure favors keratinocyte apoptosis or necroptosis, which results in the release of multiple proinflammatory cytokines, including IL-6, IL-1α, IL-1ß, TNF-α, IFNs, and CXCL10. Serum levels of IL-17 are elevated in patients with ACLE, SCLE, and DLE. Evidence suggests IL-22 plays a role primarily in tissue repair rather than in inflammation. High expression of BAFF and its receptors have been found in lesioned keratinocytes of patients with CLE, and patients with CLE have lower serum levels of the regulatory cytokines TGF-ß and IL-10. The chemokines CXCL9 and CXCL10 (CXCR3 ligands) have an increased expression among these patients, and their expression is correlated with IFNs levels. CXCR3 ligands recruit cytotoxic type I cells through this receptor, further supporting the death of keratinocytes via necroptosis with the subsequent release of eNAs perpetuating the inflammatory cycle. Interface dermatitis is characterized by the presence of CXCR3-positive lymphocytes. This review describes the leading cytokines and chemokines present in the circulation and skin that play a fundamental role in the pathogenesis of CLE.

Lymphoid follicular hyperplasia in patients with systemic lupus erythematosus after multiple cycles of rituximab.

Rituximab is indicated in some patients with refractory systemic lupus erythematosus (SLE). Occasionally, this medication is required in chronic form to maintain control of the disease. We described two patients who developed lymphoid follicular hyperplasia (LFH) after multiple cycles of rituximab and evaluated the expression of B cell activating factor belonging to the tumor necrosis factor (TNF) family (BAFF) and its receptors [BAFF-receptor (BAFF-R) and B cell maturation antigen (BCMA)], as possible factors related to lymphoid node enlargement. Two patients with SLE completed six and nine cycles of rituximab (1 g every 2 weeks) indicated each 9 months, achieving remission for 5 and 7 years, respectively, when developed prominent lymphadenopathies. Biopsies showed LFH. Haematological neoplasms were ruled out. Immunohistochemistry showed BAFF overexpression in the follicles, and moderate expression of BAFF-R confined to the mantle zone and BCMA to the germinal centre. Belimumab B cell activating factor belonging to the TNF family (anti-BAFF therapy) was started with positive effects on the clinical condition. LFH can develop in patients with SLE who received multiple cycles of rituximab. BAFF overexpression and moderate expression of BAFF-R and BCMA in lymph nodes were seen. These findings added to the improvement with the change to belimumab could suggest that LFH after cluster of differentiation (CD20) depletion therapy may be associated with a compensatory overexpression of BAFF and its receptors.

B-cell activating factor (BAFF) and its receptors' expression in pediatric nephrotic syndrome is associated with worse prognosis.

AIM: Immune pathogenesis of nephrotic syndrome (NS) is not completely understood. We aimed to evaluate the expression of B-cell activating factor (BAFF) and its receptors in renal samples from pediatric NS patients and its relationship with renal function survival. MATERIALS AND METHODS: We conducted an ambispective study on 33 patients with pediatric NS. Immunohistochemistry for BAFF, TACI, BCMA and BR3 was performed. Markers were evaluated on podocytes and interstitial inflammatory infiltrates (III). We performed Kaplan-Meier curves to describe renal function survival according to markers' expression. RESULTS: Thirty-three NS patients were included. Minimal change disease was seen in 21 (63.6%) patients, and focal segmental glomerulosclerosis in 12 (36.4%). BAFF was found in podocytes (18.2% of samples) and III (36.4% of samples), BAFF-R in one sample, TACI in 4 (podocytes and III), and BCMA in 5 samples of podocytes and 7 of III. BAFF on podocytes and III was associated with worst renal function at follow-up; those patients had 25% probability of having GFR >90 mL/min/1.73m2, versus 84.9% when absent (p = 0.0067). Patients with BAFF in III had 42.9% probability of having GFR>90 mL/min/1.73 m2, versus 94.1% when absent (p = 0.0063). CONCLUSION: BAFF expression in renal biopsies could be a prognostic factor for renal function.

Improvement of the autoimmune phenomenon after treatment of primary hyperparathyroidism: Possible role of dynamics of parathyroid hormone-1-receptor in B-lymphocytes.

We report a case of 65-year-old male patient with primary hyperparathyroidism (PHPT) who was admitted to the hospital for autoimmune manifestations (including autoimmune hepatitis and autoantibody development) and exhibited subsequent clinical and paraclinical improvement after parathyroidectomy. By flow cytometry, the expression of PTH receptor 1 (PTHR1) on B lymphocytes of peripheral blood was documented to be higher than that in healthy controls. After parathyroidectomy, autoimmune manifestations improved, while PTH1R expression on B-lymphocytes increased. The possible role of the dynamics of B-lymphocyte PTHR1 in the development of this autoimmune phenomenon is discussed.

A Patient Develops Bullous Rash After Receiving the Second Dose of COVID-19 Vaccine.

Our knowledge about the clinical spectrum of COVID-19 has continued to evolve. The clinical features of the infection and vaccine are continuously updated. We present a case of bullous pemphigoid after receiving a second dose of the COVID-19 vaccine. This case highlights autoimmune skin findings seen in a patient after COVID-19 vaccination. A 70-year-old male presented with the chief complaint of blistering skin rash. He received his second dose of Pfizer COVID-19 vaccine two days before developing a painful pruritic maculopapular rash that started on his hands and extended proximally to his trunk. Physical exam was remarkable for tense bullae with negative Nikolsky sign. Biopsy and direct immunofluorescence lead to the diagnosis of bullous pemphigoid. The lesions improved significantly with steroids. Various cutaneous eruptions have been reported with Moderna and Pfizer COVID-19 vaccines, including the new onset of bullous pemphigoid. Based on our case, we suggest that bullous pemphigoid after COVID-19 vaccination is responsive to steroids and the prognosis is excellent. Understanding the clinical course and prognosis of bullous pemphigoid from the COVID-19 vaccine is of significant importance as we strive to keep our patients and communities safe. More data is needed to better guide recommendations, but so far looking at the example from our case, the benefits of COVID-19 vaccination seem to outweigh the risks. Therefore, patients should be advised to continue with future vaccinations.

From ocular immune privilege to primary autoimmune diseases of the eye.

After the discovery of ocular immune privilege, exhaustive research has been performed, and advances have been made in the field of ocular immunology. Currently, it is clear that local and systemic pathways are involved in maintaining a well-preserved environment to guarantee normal vision. The development of autoimmunity in the eye is still a subject of research; however, it has been suggested that microglial cells could act as a gateway for initiating autoimmunity. Moreover, based on the fact that ocular involvement in systemic autoimmune diseases is well described, we aimed to collect and describe ocular diseases with a proposed primary autoimmune pathogenic mechanism. It should be noted that the autoimmune classification in several entities is a topic of discussion among authors.

Biological Effects of Animal Venoms on the Human Immune System.

Venoms are products of specialized glands and serve many living organisms to immobilize and kill prey, start digestive processes and act as a defense mechanism. Venoms affect different cells, cellular structures and tissues, such as skin, nervous, hematological, digestive, excretory and immune systems, as well as the heart, among other structures. Components of both the innate and adaptive immune systems can be stimulated or suppressed. Studying the effects on the cells and molecules produced by the immune system has been useful in many biomedical fields. The effects of venoms can be the basis for research and development of therapeutic protocols useful in the modulation of the immunological system, including different autoimmune diseases. This review focuses on the understanding of biological effects of diverse venom on the human immune system and how some of their components can be useful for the study and development of immunomodulatory drugs.

Increase in direct costs for health systems due to lupus nephritis: the case of Colombia.

OBJECTIVE: Lupus nephritis is one of the most severe complications of systemic lupus erythematosus and it has been estimated that can occur in up to 60% of patients. Direct costs of lupus nephritis have not been studied in developing countries. This study aimed to describe lupus nephritis direct costs in Colombia. METHODS: Administrative data from two Colombian health maintenance organizations for 2014 and 2015 was obtained. An algorithm based on the International Statistical Classification of Diseases and Related Health Problems 10th revision codes was developed to identify patients with lupus nephritis and lupus nephritis under study. RESULTS: The average annual per-patient, all-claims, all-cause direct cost for lupus nephritis was US$ 12,624, 7.5 times higher than the average lupus patient without lupus nephritis. For lupus nephritis cases under study, estimated direct cost was US$ 3,664, 2 times higher than average lupus patient in Colombia. Difference in lupus nephritis patients is mainly accounted for the cost and frequency of procedures, exceeding by a factor of 5 the cost for durable medical equipment and the cost for drugs, respectively. CONCLUSION: Lupus patients who progress to lupus nephritis stage increased seven-fold the average annual per-patient, all-claims, and all-cause direct cost for the Colombian health system.

Clinical Characteristics and Outcomes of Patients With ANCA-Associated Vasculitides in a Colombian Hospital.

BACKGROUND/OBJECTIVE: Antineutrophil cytoplasmic antibody-associated vasculitides (AAVs) are uncommon systemic autoimmune diseases, of which few reports exist in Latin America. Our aim was to examine AAV evaluated in a high-complexity hospital in southwestern Colombia, with emphasis in severe forms. METHODS: A medical records review study of 67 patients was performed, and data were collected from electronic registries. Moderate and severe AAVs were defined as the presence of life-threatening complications, unfavorable Birmingham Vasculitis Activity Score outcomes, and hospitalization requirements at the time of diagnosis and by the last follow-up, between 2011 and 2019. Clinical manifestations, treatment, and outcomes were evaluated. The AAV subtypes were compared. RESULTS: A total of 67 cases were included. The majority were female (n = 44, 65.67%), and the median age was 52 (40-64) years. Granulomatosis with polyangiitis (GPA) was the most frequent with 42 patients (62.68%), followed by microscopic polyangiitis (MPA) and eosinophilic GPA, with 15 patients (22.38%) and 10 patients (14.92%), respectively. Forty-four patients (65.67%) presented pulmonary symptoms. The highest Birmingham Vasculitis Activity Score corresponded to MPA, with 21 (12-25) points. Fifteen patients (22.4%) were admitted to the intensive care unit throughout the course of the disease, of whom 10 had GPA. The longest stay and duration of mechanical ventilation were seen in MPA. The principal treatments were corticosteroids and cyclophosphamide, and the main outcome was end-stage renal disease. CONCLUSIONS: In this cohort of AAV, most of cases corresponded to GPA, and pulmonary manifestations were the most common. Microscopic polyangiitis was the more severe subtype as it showed worse impairment in clinical characteristics and intensive care unit requirements.

Association of Antiribosomal P Antibody with Neurological and Systemic Manifestations in Patients with Systemic Lupus Erythematosus in Southwestern Colombia.

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by heterogeneous pathogenesis, various clinical manifestations, and a broad spectrum of autoantibodies which recognize different cellular components. This study examines the clinical significance and serological associations of serum antiribosomal P antibodies (anti-P) derived from SLE patients in a population from southwestern Colombia. METHODS: We performed a cross-sectional study of 66 SLE patients. Serum antiribosomal P0 autoantibodies were detected by line immunoassay using the ANA-LIA MAXX kit and processed on the automated HumaBlot 44FA system (Human Diagnostics, Germany). RESULTS: Of the 66 SLE patients included in the study, 17 patients (25.76%) showed anti-P positivity by line immunoassay (IA), 47 (71.21%) were negative, and results from 2 patients were indeterminate. We did not find an association with neuropsychiatric SLE (NPSLE), renal, or hepatic disorders (P > 0.05). Laboratory findings indicated that anti-P positivity was significantly associated to anti-Smith (P = 0.001), anti-Ro60/SSA (P = 0.046), and anti-dsDNA antibodies (P = 0.034), the latter being true only when performed using indirect immunofluorescence (IIF). CONCLUSION: The anti-P antibodies are not associated with clinical manifestations such as NPSLE, lupus nephritis, or hepatic involvement in the southwest Colombian SLE population. Moreover, we confirmed previously reported association between anti-P antibody, serum anti-dsDNA, and anti-Smith.

New insights into the taxonomy of autoimmune diseases based on polyautoimmunity.

OBJECTIVE: The clinical coexistence of two or more autoimmune diseases (ADs) fulfilling classification criteria is termed "overt polyautoimmunity" (PolyA), whereas the presence of autoantibodies unrelated to an index AD, without clinical criteria fulfillment, is known as "latent PolyA". We aimed to explore a new taxonomy of ADs based on PolyA. METHODS: In a cross-sectional study of 292 subjects, we evaluated the presence of PolyA in 146, 45, 29, 17, and 17 patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), autoimmune thyroid disease (AITD) and systemic sclerosis (SSc), respectively, and 38 healthy controls. Clinical assessment, autoantibody profile (by autoantigen array chip), lymphocytes immunophenotype and cytokine profile (by flow cytometry) were evaluated simultaneously. A mixed cluster methodology was used to classify ADs. RESULTS: Latent PolyA was more frequent than overt PolyA, ranging from 69.9% in RA to 100% in SSc. Nevertheless, both latent and overt PolyA clustered together. Over-expressed IgG autoantibodies were found to be hallmarks for the identification of index ADs. The combination of autoantibodies allowed high accuracy in the classification of ADs. Three well-defined clusters based on PolyA were observed with distinctive clinical and immunological phenotypes. CONCLUSIONS: This proof-of-concept study indicates that ADs can be classified according to PolyA. PolyA should be considered in all studies dealing with ADs, including epidemiological, genetic, and clinical trials.

Caracterización epidemiológica de pacientes con uveítis en el suroccidente colombiano / Epidemiological characterization of patients with uveitis in southwestern Colombia

Introducción: La etnicidad y la geografía se han descrito como determinantes de la presentación clínica de la uveítis y su etiología. Objetivo: Caracterizara los pacientes del suroccidente colombiano con uveítis. Material y métodos: Estudio retrospectivo, del 2011 al 2019, en Cali, Colombia. Se evaluaron características demográficas, clínicas, etiológicas y desenlaces de pacientes con uveítis. Resultados: Se incluyeron 144 pacientes. La edad fue 51.5 (35.2-61.7) años, 80 (55.5%) fueron mujeres. El 66% (n = 95) presentó uveítis anterior. De las manifestaciones clínicas, el ojo rojo fue la más frecuente, seguido de dolor ocular. La mayoría tuvo síntomas < 12 semanas, presentó agudeza visual de 20/20-20/40 y rangos de presión intraocular entre 10 y 22 mmHg. De las etiologías, 20 (17.9%) continuaban en estudio y 7 (6.3%) fueron no definidas/idiopáticas. Trauma se vio en 12 (10.7%), la asociada a HLA-B27 en 10 (8.9%) y toxoplasmosis en 8 (7.1%). Conclusión: Es la primera caracterización de la uveítis en el suroccidente colombiano

Background: Ethnicity and geography have been described as determinants of the clinical presentation of uveitis and its etiology. Objective: To characterize patients from southwestern Colombia with uveitis. Material and methods: Retrospective study, from 2011 to 2019, in Cali, Colombia. Demographic, clinical, etiological characteristics and outcomes of patients with uveitis were evaluated. Results: 144 patients were included. The age was 51.5 (35.2-61.7) years, 80 (55.5%) were women. 66% (n = 95) presented anterior uveitis. Of the clinical manifestations, the red eye was the most frequent, followed by ocular pain. Most had symptoms < 12 weeks, visual acuity of 20/20-20/40 and intraocular pressure ranges between 10-22 mmHg. Of the etiologies, 20 (17.9%) were still under study and 7 (6.3%) were undefined/idiopathic. Trauma was seen in 12 (10.7%), that associated with HLA-B27 in 10 (8.9%) and toxoplasmosis in 8 (7.1%). Conclusion: It is the first characterization of uveitis in southwestern Colombia.

Increase in direct costs for health systems due to lupus nephritis: the case of Colombia

ABSTRACT Objective Lupus nephritis is one of the most severe complications of systemic lupus erythematosus and it has been estimated that can occur in up to 60% of patients. Direct costs of lupus nephritis have not been studied in developing countries. This study aimed to describe lupus nephritis direct costs in Colombia. Methods Administrative data from two Colombian health maintenance organizations for 2014 and 2015 was obtained. An algorithm based on the International Statistical Classification of Diseases and Related Health Problems 10th revision codes was developed to identify patients with lupus nephritis and lupus nephritis under study. Results The average annual per-patient, all-claims, all-cause direct cost for lupus nephritis was US$ 12,624, 7.5 times higher than the average lupus patient without lupus nephritis. For lupus nephritis cases under study, estimated direct cost was US$ 3,664, 2 times higher than average lupus patient in Colombia. Difference in lupus nephritis patients is mainly accounted for the cost and frequency of procedures, exceeding by a factor of 5 the cost for durable medical equipment and the cost for drugs, respectively. Conclusion Lupus patients who progress to lupus nephritis stage increased seven-fold the average annual per-patient, all-claims, and all-cause direct cost for the Colombian health system.