Understanding the biological mechanisms underlying the pH-dependent nature of FcRn binding, as well as the various factors influencing the affinity to FcRn, was concurrent with the arrival of the first recombinant IgG monoclonal antibodies (mAbs) and IgG Fc-fusion proteins in clinical practice. IgG Fc–FcRn became a central subject of interest for the development of these drugs for the comfort of patients and good clinical responses. In this review, we describe (i) mAb mutations close to and outside the FcRn binding site, increasing the affinity for FcRn at acidic pH and leading to enhanced mAb half-life and biodistribution, and (ii) mAb mutations increasing the affinity for FcRn at acidic and neutral pH, blocking FcRn binding and resulting, in vivo, in endogenous IgG degradation. Mutations modifying FcRn binding are discussed in association with pH-dependent modulation of antigen binding and (iii) anti-FcRn mAbs, two of the latest innovations in anti-FcRn mAbs leading to endogenous IgG depletion. We discuss the pharmacological effects, the biological consequences, and advantages of targeting IgG–FcRn interactions and their application in human therapeutics.

Objective: IgA vasculitis (IgAV) can occur after vaccination. We aimed to assess a potential safety signal on the association between coronavirus disease 2019 (COVID-19) vaccines and IgAV.Methods: Cases of IgAV involving COVID-19 vaccines were retrieved in VigiBase. Disproportionate reporting was assessed using the Bayesian information component (IC) with all other drugs and vaccines as control groups.Results: Three hundred thirty patients with de novo IgAV from 24 countries were included, mostly from the United States (193/330, 58%). Fifty percent (163/328) were female and median age was 32 years (IQR 15-59), of which 33% (84/254) were young (1-17 yrs). Median time to onset of IgAV was 7 days (IQR 2-16; n = 256) and 85% (280/330) of patients were vaccinated with mRNA vaccines. Seriousness was reported in 188/324 (58%) cases. Sixty-five percent (95/147) recovered and 1% (2/147) died. A positive rechallenge was reported for 3 of 4 patients (75%). A total of 996 cases of IgAV were identified with other vaccines. There was a small significant increase in IgAV reporting with COVID-19 vaccines compared with all other drugs (IC 0.22, 95% credible interval [CrI] 0.04 to 0.35). No disproportionality signal was found between COVID-19 vaccines and other vaccines (IC −1.42, 95% CrI −1.60 to −1.28). There was no significant difference between mRNA vaccines and viral vector COVID-19 vaccines. Men and children had a significant overreporting of IgAV compared with women and adults, respectively.Conclusion: This study provides reassuring results regarding the safety of COVID-19 vaccines in the occurrence of IgAV compared to other vaccines.

Objective: Immunoglobulin A vasculitis (IgAV) usually occurs following viral respiratory tract infection. In the context of the global coronavirus disease 2019 (COVID-19) pandemic, we describe a case series of patients who developed IgAV following SARS-CoV-2 infection.Methods: This national multicenter retrospective study included patients with IgAV following SARS-CoV-2 infection from January 1, 2020, to January 1, 2022. Patients had histologically proven IgAV and reverse transcription PCR (RT-PCR)-proven SARS-CoV-2 infection. The interval between infection and vasculitis onset had to be < 4 weeks.Results: We included 5 patients, 4 of whom were women with a mean age of 45 years. Four patients had paucisymptomatic infections and 1 required a 48-hour low-flow oxygen treatment. All 5 patients had purpuric skin involvement. Arthritis was observed in 2 patients, 3 had IgA glomerulonephritis, and 2 had digestive involvement. Three renal biopsies were performed and showed mesangial IgA deposits without any extracapillary proliferation. Median C-reactive protein was 180 (range 15.1-225) mg/L, median serum creatinine level was 65 (range 41-169) µmol/L, and 2 patients had a glomerular filtration rate < 60 mL/min. Four patients received first-line treatment with glucocorticoids. All patients had a favorable progression and 2 patients experienced minor skin relapses, one after COVID-19 vaccination.Conclusion: This series describes the emergence of IgAV closely following COVID-19; we were not able to eliminate an incidental link between these events. Their disease outcomes were favorable. In most of our patients, the SARS-CoV-2 infection was paucisymptomatic, and we recommend RT-PCR tests to look for COVID-19 in patients without any evident triggers for IgAV.

Objective: The worldwide coronavirus disease 2019 (COVID-19) vaccination campaign triggered several autoimmune diseases. We hereby aimed to describe IgA vasculitis (IgAV) following COVID-19 vaccination.Methods: We conducted a national, multicenter, retrospective study in France of new-onset adult IgAV diagnosis following COVID-19 vaccination.Results: In total, 12 patients with new-onset IgAV were included. Of these, 5 (41.7%) were women, and the median age was 52.5 (IQR 30.75-60.5) years. Of the 12 patients, 10 had received an mRNA vaccine and 2 had received a viral vector vaccine. The median time from vaccination to onset of symptoms was 11.5 (IQR 4.25-21.25) days. Vasculitis occurred after the first vaccine dose in most patients (n = 8). All patients had skin involvement, with skin necrosis in 4 patients. In total, 7 patients had joint involvement and 2 had arthritis. A total of 4 patients had nonsevere gastrointestinal involvement and 2 had nonsevere renal involvement. The median C-reactive protein level was 26 (IQR 10-66.75) mg/L, the median creatininemia level was 72 (IQR 65-81) μmol/L, and 1 patient had an estimated glomerular filtration rate of less than 60 mL/min at management. All patients received treatment, including 9 patients (75%) who received glucocorticoids. In total, 5 patients received a vaccine dose after developing IgAV, 1 of whom experienced a minor cutaneous relapse.Conclusion: The baseline presentation of IgAV following COVID-19 vaccination was mild to moderate, and outcomes were favorable. Thus, a complete COVID-19 vaccination regimen should be completed in this population. Of note, a fortuitous link cannot be ruled out, requiring a worldwide pharmacovigilance search to confirm these findings.

The neonatal Fc receptor (FcRn) is a ubiquitously expressed protein historically involved in IgG and albumin recycling. Recent data suggest an involvement in the pathophysiology of antibody-mediated autoimmune diseases. Among them, systemic lupus erythematosus (SLE) implies clinical and biological abnormalities of innate and adaptive circulating immune cells, potentially involving newly described functions of FcRn. In this study, FcRn expression was assessed by flow cytometry in peripheral blood leukocytes of 41 SLE patients with either active or inactive disease and 32 healthy donors. FcRn expression in B cells, natural killer cells, and T cells of SLE patients was statistically lower as compared to healthy donors. Conversely, FcRn level was statistically higher in non-classical monocyte subpopulations (CD14+CD16+ monocytes) of SLE patients versus healthy donors providing an interesting perspective to further explore its role in SLE pathophysiology.

Since the neonatal IgG Fc receptor (FcRn) was discovered, its role has evolved from immunoglobulin recycling and biodistribution to antigen presentation and immune complex routing, bringing it to the center of both humoral and cellular immune responses. FcRn is thus involved in the pathophysiology of immune-related diseases such as cancer, infection, and autoimmune disorders. This review focuses on the role of FcRn in autoimmunity, based on the available data from both animal models and human studies. The knowledge concerning ways in which FcRn is involved in autoimmune response has led to the development of inhibitors for the treatment of autoimmune diseases, also described here. Up to date, the literature remains scarce, shedding light on the need for further studies to fully understand the various pathophysiological roles of this unique receptor.