Search

Organ-specific autoimmunity is often characterized by autoantibodies targeting proteins expressed in the affected tissue. A subgroup of autoimmunopathies has recently emerged that is characterized by predominant autoantibodies of the IgG4 subclass (IgG4-autoimmune diseases; IgG4-AID). This group includes pemphigus vulgaris, thrombotic thrombocytopenic purpura, subtypes of autoimmune encephalitis, inflammatory neuropathies, myasthenia gravis and membranous nephropathy. Although the associated autoantibodies target specific antigens in different organs and thus cause diverse syndromes and diseases, they share surprising similarities in genetic predisposition, disease mechanisms, clinical course and response to therapies. IgG4-AID appear to be distinct from another group of rare immune diseases associated with IgG4, which are the IgG4-related diseases (IgG4-RLD), such as IgG4-related which have distinct clinical and serological properties and are not characterized by antigen-specific IgG4. Importantly, IgG4-AID differ significantly from diseases associated with IgG1 autoantibodies targeting the same organ. This may be due to the unique functional characteristics of IgG4 autoantibodies (e.g. anti-inflammatory and functionally monovalent) that affect how the antibodies cause disease, and the differential response to immunotherapies of the IgG4 producing B cells/plasmablasts. These clinical and pathophysiological clues give important insight in the immunopathogenesis of IgG4-AID. Understanding IgG4 immunobiology is a key step towards the development of novel, IgG4 specific treatments. In this review we therefore summarize current knowledge on IgG4 regulation, the relevance of class switching in the context of health and disease, describe the cellular mechanisms involved in IgG4 production and provide an overview of treatment responses in IgG4-AID. Copyright © 2022 Koneczny, Tzartos, Mané-Damas, Yilmaz, Huijbers, Lazaridis, Höftberger, Tüzün, Martinez-Martinez, Tzartos and Leypoldt.

IgG4 autoimmune diseases (IgG4-AID) are an emerging group of autoimmune diseases that are caused by pathogenic autoantibodies of the IgG4 subclass. It has only recently been appreciated, that members of this group share relevant immunobiological and therapeutic aspects even though different antigens, tissues and organs are affected: glomerulonephritis (kidney), pemphigus vulgaris (skin), thrombotic thrombocytopenic purpura (hematologic system) muscle-specific kinase (MuSK) in myasthenia gravis (peripheral nervous system) and autoimmune encephalitis (central nervous system) to give some examples. In all these diseases, patients’ IgG4 subclass autoantibodies block protein-protein interactions instead of causing complement mediated tissue injury, patients respond favorably to rituximab and share a genetic predisposition: at least five HLA class II genes have been reported in individual studies to be associated with several different IgG4-AID. This suggests a role for the HLA class II region and specifically the DRβ1 chain for aberrant priming of autoreactive T-cells toward a chronic immune response skewed toward the production of IgG4 subclass autoantibodies. The aim of this review is to provide an update on findings arguing for a common pathogenic mechanism in IgG4-AID in general and to provide hypotheses about the role of distinct HLA haplotypes, T-cells and cytokines in IgG4-AID. © Copyright © 2021 Koneczny, Yilmaz, Lazaridis, Tzartos, Lenz, Tzartos, Tüzün and Leypoldt.

Objective: The aim of this study was (1) to investigate the prevalence of movement disorders in a large cohort of patients with encephalitis with LGI1 and CASPR2 antibodies and (2) to compare clinical phenomenology between patients with Caspr2 and LGI1 antibodies. Background: Movement disorders are a common clinical feature in NMDAR encephalitis. However, their frequency and phenomenology in other common antibody‐defined autoimmune encephalitis subtypes is less well studied. Autoimmune encephalitis with antibodies targeting the neuronal proteins LGI1 or CASPR2 are other frequently observed neuronal autoantibodies in patients with autoimmune encephalitis. Methods: Retrospective analysis of 280 patients from 5 different referral centers with encephalitis and antibodies against LGI1 or CASPR2 in serum and/or CSF was performed with a focus on the clinical presence of movement disorders. Results: FBDS were observed in 25.5% of patients with LGI1 antibodies while other movement disorders (chorea 1.9%, myoclonus 1.9%, tremor 0.9%) were rare or absent (ataxia, tics, dystonia and parkinsonism). In contrast patients with Caspr2 antibodies presented significantly more frequent with ataxia (23%, p = Prominent myoclonus was found in 22 patients with Caspr2 antibodies. In 2 patients myoclonus was the only clinical finding in the context of Caspr2 autoimmunity while in the remaining patients myoclonus presented in combination with well‐known anti–Caspr2 antibody‐related syndromes. However, myoclonus was the presenting symptom in 40.9% (n=9) patients. Topographically, myoclonus was generalized in 36.4% (n=8), multifocal in 40.9% (n=9 [6 lower limbs, 3 upper limbs]) and segmental in 9% (n=2) of patients. In the majority of patients (59.1%, n=13) myoclonus was aggravated or exclusively triggered by orthostatism (76.9%, n=10) and/or walking (38.5%, n=5). In 27.3% (n=6) myoclonus presented as a pure paroxysmal kinesiogenic movement disorder. Immunotherapy lead to complete allevation or major improvement of myoclonus in 81.8% (n=18). Conclusions: Movement disorders are a common feature in patients with autoimmune encephalitis with LGI1 and CASPR2 antibodies. Interestingly, the pattern of movement disorders differed between patient groups, which could help to guide diagnosis.

CD4+ T cells reactive against SARS-CoV-2 can be found in unexposed individuals, and these are suggested to arise in response to common cold coronavirus (CCCoV) infection. Here, we utilized SARS-CoV-2-reactive CD4+ T cell enrichment to examine the antigen avidity and clonality of these cells, as well as the relative contribution of CCCoV cross-reactivity. SARS-CoV-2-reactive CD4+ memory T cells were present in virtually all unexposed individuals examined, displaying low functional avidity and multiple, highly variable cross-reactivities that were not restricted to CCCoVs. SARS-CoV-2-reactive CD4+ T cells from COVID-19 patients lacked cross-reactivity to CCCoVs, irrespective of strong memory T cell responses against CCCoV in all donors analyzed. In severe but not mild COVID-19, SARS-CoV-2-specific T cells displayed low functional avidity and clonality, despite increased frequencies. Our findings identify low-avidity CD4+ T cell responses as a hallmark of severe COVID-19 and argue against a protective role for CCCoV-reactive T cells in SARS-CoV-2 infection.

Objective: To report a large cohort of patients with antibodies against contactin-associated protein-like 2 (Caspr2) and provide the clinical spectrum of this disorder. Methods: Serum and CSF samples were assessed at 2 neuroimmunology centers in Barcelona and Rotterdam. Patients were included if Caspr2 antibodies were confirmed with 2 independent techniques, including brain immunohistochemistry and cell-based assay. Clinical information was obtained by the authors or provided by treating physicians after patients' informed consent. Results: Median age at symptom onset was 66 years. Of 38 patients, 34 were male. Median time to nadir of disease was 4 months (in 30% >1 year). The most frequent syndromes included limbic encephalitis (42%) and Morvan syndrome (29%). Seventy-seven percent of the patients had >= 3 of the following symptoms: encephalopathy (cognitive deficits/seizures), cerebellar dysfunction, peripheral nervous system hyperexcitability, dysautonomia, insomnia, neuropathic pain, or weight loss. A tumor, mostly thymoma, occurred in 19% of the patients. Immunoglobulin G4 subclass antibodies were present in all patients; 63% also had immunoglobulin G1 antibodies. Treatment response occurred in 93% of the patients and 25% had clinical relapses. Conclusions: Caspr2 antibodies associate with a treatable disorder that predominantly affects elderly men. The resulting syndrome may vary among patients but it usually includes a set of well-established symptoms. Recognition of this spectrum of symptoms and consideration of the protracted clinical course are important for early diagnosis of this disorder. Prompt immunotherapy and tumor therapy (if needed) often result in improvement.

Hintergrund: Isolierte cerebelläre Syndrome ohne zugrunde liegende opportunistische Infektionen, hereditäre oder metabolische Ursachen oder HIV-Encephalopathie sind selten, ihre Genese weitgehend unklar. Methodik: Es werden die Charakteristika zweier Patienten mit subakut aufgetretenen [for full text, please go to the a.m. URL], 10. Kongress für Infektionskrankheiten und Tropenmedizin (KIT 2010)