Acute exacerbation of immunoglobulin A nephropathy complicated by alveolar hemorrhage after coronavirus disease 2019 vaccination: A case report.

RATIONALE: Reports have suggested a relationship between coronavirus disease 2019 (COVID-19) vaccination and new-onset or recurring renal diseases, of which immunoglobulin A (IgA) nephropathy is a representative disease. Alveolar hemorrhage in patients with IgA nephropathy is rare but reportedly has a high mortality and morbidity. To our knowledge, there have been no reports regarding the development of IgA nephropathy with alveolar hemorrhage following COVID-19 vaccination. PATIENTS CONCERN: A 23-year-old Japanese man presented with hemoptysis and peripheral edema a few days after receiving a second dose of a COVID-19 mRNA vaccine. Severe renal failure and alveolar hemorrhage were noted thereafter, and renal biopsy showed crescentic glomerulonephritis with mesangial proliferation accompanied by mesangial electron-dense deposits containing IgA. Renal biopsy tissue also showed chronic histological changes suggestive of acute exacerbation of preexisting IgA nephropathy. DIAGNOSIS: The diagnosis of IgA nephropathy complicated by alveolar hemorrhage was made. INTERVENTIONS AND OUTCOMES: Renal function did not recover despite treatment with high-dose steroids; the patient was maintained on hemodialysis and eventually underwent successful renal transplantation. LESSONS: The present case suggested that although extremely rare, severe renal failure requiring renal replacement therapy could occur in patients with IgA nephropathy after COVID-19 vaccination. Future accumulation of similar cases is needed to predict the risk of renal injury following vaccination.

Changes in intestinal homeostasis and immunity in a cigarette smoke- and LPS-induced murine model for COPD: the lung-gut axis.

Chronic obstructive pulmonary disease (COPD) is often associated with intestinal comorbidities. In this study, changes in intestinal homeostasis and immunity in a cigarette smoke (CS)- and lipopolysaccharide (LPS)-induced COPD model were investigated. Mice were exposed to cigarette smoke or air for 72 days, except days 42, 52, and 62 on which the mice were treated with saline or LPS via intratracheal instillation. Cigarette smoke exposure increased the airway inflammatory cell numbers, mucus production, and different inflammatory mediators, including C-reactive protein (CRP) and keratinocyte-derived chemokine (KC), in bronchoalveolar lavage (BAL) fluid and serum. LPS did not further impact airway inflammatory cell numbers or mucus production but decreased inflammatory mediator levels in BAL fluid. T helper (Th) 1 cells were enhanced in the spleen after cigarette smoke exposure; however, in combination with LPS, cigarette exposure caused an increase in Th1 and Th2 cells. Histomorphological changes were observed in the proximal small intestine after cigarette smoke exposure, and addition of LPS had no effect. Cigarette smoke activated the intestinal immune network for IgA production in the distal small intestine that was associated with increased fecal sIgA levels and enlargement of Peyer's patches. Cigarette smoke plus LPS decreased fecal sIgA levels and the size of Peyer's patches. In conclusion, cigarette smoke with or without LPS affects intestinal health as observed by changes in intestinal histomorphology and immune network for IgA production. Elevated systemic mediators might play a role in the lung-gut cross talk. These findings contribute to a better understanding of intestinal disorders related to COPD.

Therapeutic immunoglobulin A antibody for dysbiosis-related diseases.

Dysbiosis is alterations in the microbial composition compared with a healthy microbiota and often features a reduction in gut microbial diversity and a change in microbial taxa. Dysbiosis, especially in the gut, has also been proposed to play a crucial role in the pathogenesis of a wide variety of diseases, including inflammatory bowel disease, colorectal cancer, cardiovascular disease, obesity, diabetes and multiple sclerosis. A body of evidence has shown that intestinal polymeric immunoglobulin A (IgA) antibodies are important to regulate the gut microbiota as well as to exclude pathogenic bacteria or viral infection such as influenza and SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) at mucosal sites. Since the 1970s, trials for oral administration of therapeutic IgA or IgG have been performed mainly to treat infectious enteritis caused by pathogenic Escherichia coli or Clostridium difficile. However, few of them have been successfully developed for clinical application up to now. In addition to the protective function against intestinal pathogens, IgA is well known to modulate the gut commensal microbiota leading to symbiosis. Nevertheless, the development of therapeutic IgA drugs to treat dysbiosis is not progressing. In this review, the advantages of therapeutic IgA antibodies and the problems for their development will be discussed.

Características de algunos parámetros de la inmunidad humoral y celular en pacientes con linfedema / Characteristics of some humoral and cellular immunity´s parameters in patients with lymphedema

Introducción: El linfedema es una enfermedad crónica con un impacto negativo sobre la salud de las personas que lo padecen. Este se considera un problema de salud subestimado y subregistrado, por lo que requiere de mayores esfuerzos investigativos y sanitarios. Objetivo: Identificar las características de algunos parámetros de la inmunidad humoral y celular en pacientes con linfedema del municipio El Cerro. Métodos: Se realizó un estudio descriptivo en 48 pacientes residentes en el municipio Cerro, atendidos en consulta externa del Instituto Nacional de Angiología y Cirugía Vascular en el período 2011-2015. El grupo se dividió en 24 pacientes con linfedema y 24 sin la enfermedad. A todos se les cuantificaron las concentraciones de las inmunoglobulinas (A, G y M) y de la proteína C reactiva. También se les hizo la prueba de hipersensibilidad retardada. Se utilizó chi cuadrado no paramétrico para asociar el estado inmunológico con la presencia de linfedema, la etiología y los estadios de este. Se trabajó con una confiabilidad del 95 por ciento (p < 0,05). Resultados: Predominaron los pacientes del sexo femenino (58,3 por ciento) y los de 60 años y más (29,2 por ciento). Hubo mayor frecuencia de linfangitis recurrentes (70,8 por ciento), con predominio del linfedema secundario en estadio IIb (45,8 por ciento); de afectación del miembro inferior derecho (45,8 por ciento), con una diferencia significativa de las inmunoglobulinas (IgA e IgG); y de frecuencia de pacientes anérgicos (91,7 por ciento), con proteína C reactiva positiva (45,8 por ciento). Conclusiones: Los pacientes con linfedema tienen afectados su sistema inmune, con mayor frecuencia de anérgicos, diminución de las inmunoglobulinas IgA e IgG, y positividad de proteína C reactiva(AU)

Introduction: Lymphedema is a chronic disease with a negative impact on the health of patients with lymphedema. It is considered an underestimated and sub-recorded health problem, which requires greater research and health efforts. Objective: Identify the characteristics of some parameters of humoral and cellular immunity in patients with lymphedema from Cerro municipality. Methods: A descriptive study was carried out in 48 patients living in Cerro municipality, who were attended in the external consultation of the National Institute of Angiology and Vascular Surgery in the period 2011-2015. The group was divided into 24 patients with lymphedema and 24 patients without the disease. The concentrations of immunoglobulins (A, G and M) and C-reactive protein were quantified in all of them. The test of delayed hypersensitivity was also perfomed. Non-parametric chi-square was used to associate immune state with the presence of lymphedema, etiology and lymphedema stages. Reliability was of 95 percent (p<0.05). Results: Female patients predominated (58.3 percent) and those of 60 years and older (29.2 percent). There was a higher frequency of recurrent lymphangitis (70.8 percent), predominantly stage II b secondary lymphedema (45.8 percent); lower right limb involvement (45.8 percent), with a significant difference of immunoglobulins (IgA and IgG); and frequency of anergic patients (91.7 percent), with positive C-reactive protein (45.8 percent). Conclusions: Patients with lymphedema have their immune system affected, more frequently the anergic ones, a decrease of IgA and IgG immunoglobulins, and positivity of C-reactive protein(AU)

When Therapeutic IgA Antibodies Might Come of Age.

BACKGROUND: Extensive efforts have been made in optimizing monoclonal immunoglobulin (Ig)G antibodies for use in clinical practice. Accumulating evidence suggests that IgA or anti-FcαRI could also represent an exciting avenue toward novel therapeutic strategies. SUMMARY: Here, we underline that IgA is more effective in recruiting neutrophils for tumor cell killing and is potently active against several pathogens, including rotavirus, poliovirus, influenza virus, and SARS-CoV-2. IgA could also be used to modulate excessive immune responses in inflammatory diseases. Furthermore, secretory IgA is emerging as a major regulator of gut microbiota, which impacts intestinal homeostasis and global health as well. As such, IgA could be used to promote a healthy microbiota in a therapeutic setting. Key messages: IgA combines multifaceted functions that can be desirable for immunotherapy.

Diffuse Alveolar Hemorrhage in IgA Vasculitis with an Atypical Presentation.

IgA vasculitis (IgAV) commonly occurs in young children, who present with a tetrad of purpura, abdominal pain, arthralgia and nephritis. Diffuse alveolar hemorrhage (DAH) is a rare complication of IgAV. We herein report an adult case of IgAV with a presentation of DAH and nephritis (pulmonary renal syndrome, PRS), but without other typical manifestations, such as purpura, abdominal pain and arthralgia. A 33-year-old man presented with hemoptysis and a low-grade fever and was diagnosed to have IgAV based on the results of a renal biopsy. Treatment with corticosteroids, cyclophosphamide, and plasmapheresis was effective. IgAV should therefore be considered in the differential diagnosis of adult PRS.

[Unrelated donor stem cell transplantation in children: low toxicity using a GvHD-prophylaxis regimen with CSA, MTX, metronidazole,iv-immunoglobulin and ATG]. / Hämatopoetische Stammzelltransplantation vom Fremdspender bei Kindern: Niedrige Toxizität durch GvHD-Prophylaxe mit CSA, MTX, Metronidazol, iv-Immunglobulin und ATG.

BACKGROUND: Unrelated donor (UD) hematopoietic stem cell transplantation (HSCT) is accepted as a therapy for leukaemic diseases and varying inborn diseases if a suitable related donor cannot be found. The goal of immunosuppressive therapy with UD-HSCT is an effective prevention of graft-versus-host-disease (GvHD) on one hand. On the other hand an optimal balance with immunocompetence of the transplanted bone marrow is desirable in order to prevent graft failure, infection and, in the case of leukaemic diseases, potentially control the underlying disease. PATIENTS AND METHODS: Between 1992 and 2000 49 patients aged 11 months to 16.7 years received an UD-HSCT in Hamburg. Underlying diseases were leukaemia or MDS in 35, of these ALL in 21, hemophagocytic lymphohistiocytosis (HLH) in 9, immunodeficiency or inborn error of metabolism in 5 patients. GvHD-prophylaxis consisted of a combination of Cyclosporin A (CSA), methotrexate (MTX), metronidazole, IgM-enriched iv-immunoglobulin (ivIg) (Pentaglobin(R)) or ivIgG and anti-thymocyte-globulin (ATG). Within the same time span 10 patients with ALL received a matched related donor HSCT (MRD-HSCT). GvHD-prophylaxis in these patients was done without ATG in 8 of 10 cases. UD-HSCT were analyzed for survival, relapse and toxicity. Probability of survival of the patients with ALL after UD-HSCT was compared with results of MRD-HSCT in children with ALL. RESULTS: The Kaplan-Meier estimates of three year overall-survival (OS) were 74 % for all patients. Probability of disease-free survival (DFS) at three years was 62 % for leukaemia/MDS-patients and 100 % for the HLH-patients. Acute GvHD (aGvHD) grades II or III occurred in 51 % of patients. Chronic GvHD (cGvHD) occurred in 22 % of patients. There were 5 cases of treatment-related mortality (TRM). Probability of DFS for patients with ALL at three years was 65 % after UD-HSCT and 30 % in the patients after MRD-HSCT. CONCLUSIONS: UD-HSCT in children is an effective and safe therapy. A GvHD-prophylaxis regimen combining the standard immunosuppressive agents CSA and MTX with ivIg, metronidazole and serotherapy using ATG may result in a low incidence of severe GvHD-complications and low TRM rate without increase in relapse rates.

Gut mucosa barrier preservation by orally administered IgA-IgG to patients undergoing bone marrow transplantation: a randomised pilot study.

Intensive cytotoxic therapy with bone-marrow transplantation (BMT) allows a potential cure for haematological malignancies. Protective strategies to minimise haematological toxicities have been successful and currently toxicity to the gastro-intestinal tract is the major cause of treatment-related morbidity and the dose-limiting factor that prevents further dose escalation. In a randomised, placebo-controlled trial we investigated whether an oral immunoglobulin preparation (IgA-IgG) can diminish intestinal toxicity with autologous BMT. IgA-IgG (n = 6) and placebo (n = 7) were orally administered from 1 day prior to the start until 1 week after the termination of the cytotoxic treatment (a total of 14 days). Intestinal toxicity was assessed by a 51Cr-EDTA absorption test for intestinal permeability and by the clinical criteria laid down by the WHO for the period before the start of the cytotoxic treatment, 1 day prior to stem-cell infusion and 4, 7, 10 and 14 days after stem-cell infusion. In the placebo group there was a significant increase in intestinal permeability on day 4 (P < 0.005) and on day 7 (P < 0.05) after stem-cell infusion, compared with the baseline, which was not seen for IgA-IgG. In addition, patients receiving IgA-IgG had significantly less intestinal permeability on day 4 (P < 0.05) and on day 7 (P < 0.05), compared with the placebo group. No significant, positive effect as regards clinical toxicity was observed. Oral administration of IgA-IgG to patients undergoing intensive cytotoxic therapy prior to BMT seems to have a protective effect on the gut mucosa barrier which is normally disrupted by this therapy.

Comportamiento de algunos paramteros determinantes de efectos adversos inducidos por inmunoglobulinas intravenosas / Performance of some determinant parameters of intravenous immnuglobulin-induced adverse effects

Los analisis de laboratorio de las inmunoglobulinas intravenosas ofrecen informacion sobre 3 aspectos fundamentales: seguridad, estabilidad y eficacia. En este estudio se analizan las variables que pueden determinar reacciones adversas, entre las mas importantes se pueden citar los niveles de inmunoglobulina A, inmunoglobulina E, activadores de la precalicreina, agregados de inmunoglobulina G, isoaglutinina y activacion espontanea del complemento. Los bajos niveles de contaminantes estan de acuerdo con el pequeno porcentaje de reacciones secundarias encontradas con su uso clinico

Phase Ia trial of murine immunoglobulin A antitransferrin receptor antibody 42/6.

In preclinical in vitro and in vivo systems, mAbs to human transferrin (Tf) receptors blocked iron uptake from Tf and showed antitumor activity. However, Tf receptors are also displayed by normal tissues, and a large, soluble pool of circulating serum Tf receptors has been detected. We report results of a Phase Ia trial of IgA monoclonal anti-Tf receptor antibody 42/6. Twenty-seven patients with advanced refractory cancer received 33 treatments with 42/6 administered as a 24-h infusion at doses ranging from 2.5 to 300 mg/m2. 42/6 was generally well tolerated, although one patient receiving a second treatment experienced an allergic-type response associated with a human antimouse antibody response. Three patients with hematological cancers showed mixed tumor responses; there were no partial or complete remissions. Peak serum levels of antibody were obtained at the termination of the 24-h infusion. At doses >/=25 mg/m2, there was a linear relationship between the 42/6 dose and average peak serum 42/6 levels ranging from <1 to 36 microgram/ml. Serum Tf receptors showed a dose-dependent decrease during 42/6 infusion to 20-30% of baseline, and remained depressed for at least 48 h after terminating the infusion. Serum 42/6 levels rose in an inverse relationship to the drop in Tf receptors. 42/6 induced an increase in serum iron and Tf saturation consistent with blockade of peripheral iron uptake, and reduced Tf receptor display by bone marrow cells. Human antimouse antibody was detected in nine patients. Anti-Tf receptor antibody was well tolerated and mediated in vivo effects on iron uptake and Tf display. Antibody concentrations capable of inhibiting malignant blood cell growth were obtained without toxicity. This represents the first clinical trial of an IgA mouse mAb, and one of only a few trials in which an antibody reacting with a broad range of normal tissues has been administered. Additional clinical trials of anti-Tf receptor antibodies in blood cell cancers are indicated.