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Clin Case Rep. 2022 Mar 23;10(3):e05602. doi: 10.1002/ccr3.5602. eCollection 2022 Mar.

ABSTRACT

Common variable immunodeficiency (CVID) is a primary immunodeficiency disease. We present a case of a patient with CVID complicated by rhinosinusitis with granulomatous inflammation. Treatment for this patient was challenging with regards recognition of the granulomatous manifestation as well as treatment in the setting immunodeficiency and was ultimately unsuccessful.

PMID:35356174 | PMC:PMC8943115 | DOI:10.1002/ccr3.5602

Br J Haematol. 2022 Mar 30. doi: 10.1111/bjh.18159. Online ahead of print.

ABSTRACT

X-linked lymphoproliferative disease (XLP1) is a rare primary immunodeficiency that usually presents in early childhood. Patients with XLP1 have been reported to have absent NKT cells, and it has been suggested that this can be diagnostic for the disorder. Whilst NKT frequency in adults is variable, little is known about their frequency in children. Therefore, we established a paediatric reference range for these cells. In contrast to previous reports, in our cohort of XLP1 patients, NKT cell numbers were found to be variable, and we would advise against using the finding of NKT cells to exclude a diagnosis of XLP1.

PMID:35355252 | DOI:10.1111/bjh.18159

Cell Rep. 2022 Mar 29;38(13):110583. doi: 10.1016/j.celrep.2022.110583.

ABSTRACT

In mature B cells, TACI controls class-switch recombination and differentiation into plasma cells during T cell-independent antibody responses. TACI binds the ligands BAFF and APRIL. Approximately 10% of patients with common variable immunodeficiency (CVID) carry TACI mutations, of which A181E and C172Y are in the transmembrane domain. Residues A181 and C172 are located on distinct sides of the transmembrane helix, which is predicted by molecular modeling to spontaneously assemble into trimers and dimers. In human B cells, these mutations impair ligand-dependent (C172Y) and -independent (A181E) TACI multimerization and signaling, as well as TACI-enhanced proliferation and/or IgA production. Genetic inactivation of TACI in primary human B cells impaired survival of CpG-activated cells in the absence of ligand. These results identify the transmembrane region of TACI as an active interface for TACI multimerization in signal transduction, in particular for ligand-independent signals. These functions are perturbed by CVID-associated mutations.

PMID:35354034 | DOI:10.1016/j.celrep.2022.110583

Clin Exp Allergy. 2022 Mar 30. doi: 10.1111/cea.14140. Online ahead of print.

ABSTRACT

BACKGROUND: The progression of chronic destructive lung disease in patients with humoral immunodeficiency (ID) and concomitant development of bronchiectasis is difficult to prevent. Lung function tests in these patients typically show bronchial obstruction of the small airways in combination with increased air trapping in the distal airways, which is consistent with small airway dysfunction.

OBJECTIVE: To assess the grade of chronic lower airway inflammation and small airway dysfunction from induced sputum and the corresponding local pro-inflammatory mediator pattern to discriminate patients affected by Bronchiectasis-related Small Airway Dysfunction (SAD).

METHODS: In a prospective design, 22 patients with ID (14 CVID, 3 XLA, 3 hyper-IgM syndrome, 1 hyper-IgE syndrome and low IgG levels due to treatment with rituximab, and 1 SCID after BMT and persistent humoral defect) and 21 healthy controls were examined. Lung function, Fraction Expiratory Nitric Oxide (FeNO) and pro-inflammatory cytokine levels were compared in subsets of patients with (ID+BE) and without bronchiectasis (ID) pre-stratified using high-resolution computed tomography (HRCT) scans and control subjects.

RESULTS: Analysis of induced sputum showed significantly increased total cell counts and severe neutrophilic inflammation in ID. The concomitant SAD revealed higher total cell numbers compared to ID. Bronchial inflammation in ID is clearly mirrored by proinflammatory mediators IL-1β, IL-6, and CXCL-8, while TNF-α revealed a correlation with lung function parameters altered in the context of Bronchiectasis-related Small Airway Dysfunction.

CONCLUSIONS: In spite of immunoglobulin substitution, bronchial inflammation was dominated by neutrophils and was highly increased in patients with ID+BE. Notably, the pro-inflammatory cytokines in patients with ID were significantly increased in induced sputum. The context-dependent cytokine pattern in relation to the presence of concomitant bronchiectasis associated with SAD in ID patients could be helpful in delimiting ID patient subgroups and individualizing therapeutic approaches.

PMID:35353925 | DOI:10.1111/cea.14140

Clin Immunol. 2022 Mar 26:108988. doi: 10.1016/j.clim.2022.108988. Online ahead of print.

ABSTRACT

Hyper IgE syndromes (HIESs) are a group of rare inborn errors of immunity with a triad of eczema, increase susceptibility to sinopulmonary and skin infections with high level of IgE serum. Although most of HIESs are sporadic, hereditary types of these disorders have been studied well. There are several distinct immunodeficiency disorders which are phenotypically similar to HIES, and thus make the diagnosis of HIES challenging. In fact, the diagnosis of HIES is typically based on the clinical suspicion and immunological assessments. There is yet no specific curative treatment for most of HIESs at present, and the treatments are mostly standing on early diagnosis and preventive therapies. For instance, the genetic diagnosis is an important module, while, due to DOCK8 mutations, the hematopoietic stem cell transplantation is necessary for patients with autosomal recessive form of HIESs. Herein, we overview HIESs, highlight their peculiar clinical and laboratory features, and finally suggest a practical forthright diagnostic chart for clinical purposes.

PMID:35351598 | DOI:10.1016/j.clim.2022.108988

Clin Exp Rheumatol. 2022 Mar 28. Online ahead of print.

ABSTRACT

OBJECTIVES: To perform a systematic literature review (SLR) on the association of common variable immunodeficiency (CVID) and rare and complex connective tissue and musculoskeletal diseases, namely systemic lupus erythematosus (SLE), Sjögren’s syndrome (SS), idiopathic inflammatory myopathies (IIM), systemic sclerosis (SSc), relapsing polychondritis, antiphospholipid syndrome, immunoglobulin (Ig) G4-related disease, as well as undifferentiated and mixed connective tissue disease.

METHODS: An SLR on studies and cases about the association of CVID and rare and complex connective tissue and musculoskeletal diseases was performed. Animal studies were excluded.

RESULTS: 170 publications fulfilled the inclusion criteria. Sjögren’s syndrome was the most frequent connective tissue disease in CVID-patients. Most case reports exist on SLE and CVID with SLE mostly preceding the manifestation of CVID. Multiple cases were published reporting the concurrence of CVID and inclusion body myositis and single cases were found on CVID and antisynthetase syndrome, polymyositis, limited SSc and relapsing polychondritis, respectively. There are no cases of CVID and antiphospholipid syndrome, IgG4-related disease, as well as undifferentiated and mixed connective tissue disease.

CONCLUSIONS: The concurrence of CVID and complex connective tissue and musculoskeletal diseases, especially SS, IIM, SSc and relapsing polychondritis is rare but relevant. The measurements of Ig-levels should be performed before the initiation of immunosuppressive therapy to allow for the differentiation of primary and secondary Ig-deficiency and substitute IG if necessary.

PMID:35349404

Zhejiang Da Xue Xue Bao Yi Xue Ban. 2021 Dec 25;50(6):783-794. doi: 10.3724/zdxbyxb-2021-0072.

ABSTRACT

Primary Sjögren syndrome is an autoimmune disease, in which a large number of lymphocytes infiltrate the exocrine glands and cause gland dysfunction. Its pathogenesis is related to the chronic inflammation of the exocrine glands caused by genetic factors, immunodeficiency or viral infection. Long-term inflammation leads to accelerated apoptosis of epithelial cells, disordered gland structure, increased expression of proinflammatory cytokine such as CXC subfamily ligand (CXCL) 12, CXCL13, B cell-activating factor (BAF), interleukin (IL)-6, interferon (IFN)-γ and tumor necrosis factor (TNF)-α in submandibular gland. With the action of antigen-presenting cells such as dendritic cells and macrophages, lymphocytes (mainly B cells) are induced to mature in secondary lymphoid organs and migrate to the submandibular gland to promotes the formation of germinal centers and the synthesis of autoantibodies. Meanwhile, innate lymphocytes, vascular endothelial cells and mucosa-associated constant T cells as important immune cells, also participated in the inflammatory response of the submandibular gland in primary Sjögren syndrome through different mechanisms. This process involves the activation of multiple signal pathways such as JAK/STAT, MAPK/ERK, PI3K/AKT/mTOR, PD-1/PD-L1, TLR/MyD88/NF-κB, BAF/BAF-R and IFN. These signaling pathways interact with each other and are intricately complex, causing lymphocytes to continuously activate and invade the submandibular glands. This article reviews the latest literature to clarify the mechanism of submandibular gland inflammation in primary Sjögren syndrome, and to provide insights for further research.

PMID:35347914 | DOI:10.3724/zdxbyxb-2021-0072

Eur J Immunol. 2022 Mar 26. doi: 10.1002/eji.202149530. Online ahead of print.

ABSTRACT

The intestinal tract is the largest immunological organ in the body and has a central function of regulating local immune responses, as the intestinal epithelial barrier is a location where the immune system interacts with the gut microbiome including bacteria, fungi and viruses. Impaired immunity in the intestinal tract can lead to immunopathology, which manifests in different diseases such as inflammatory bowel disease (IBD) or intestinal graft-versus-host disease (GVHD). A disturbed communication between epithelial cells, immune cells and microbiome will shape pathogenic immune responses to antigens, which need to be counterbalanced by tolerogenic mechanisms and repair mechanisms. Here, we review how impaired intestinal immune function leads to immunopathology with a specific focus on innate immune cells, the role of the microbiome and the resulting clinical manifestations including intestinal GVHD, IBD and enteropathy in primary immunodeficiency. This article is protected by copyright. All rights reserved.

PMID:35339113 | DOI:10.1002/eji.202149530

Vaccines (Basel). 2022 Feb 23;10(3):347. doi: 10.3390/vaccines10030347.

ABSTRACT

Immunization for the generation of protective antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged to be highly effective in preventing hospital admission, need for intensive care treatment and high mortality in the current SARS-CoV-2 pandemic. Lateral flow immune assays (LFIAs) offer a simple and competitive option to monitor antibody production after vaccination. Here, we compared the diagnostic performance of three different lateral flow assays in detecting nucleocapsid protein (NP), S1 subunit (S1) and receptor binding domain (pseudo)-neutralizing antibodies (nRBD) in sera of 107 health care workers prior (V1), two weeks (V2) after first vaccination with BNT162b2 as well as three weeks (V3) and eight months later (V4). In sera at V1, overall specificity was >99%. At V3, LFIAs showed sensitivities between 98.1 and 100%. The comparison of S1 and nRBD LFIA with S1 ELISA and a focus reduction neutralization assay (FRNT) revealed high concordance at V3. Thus, the use of lateral flow immunoassays appears to have reasonable application in the short-term follow-up after vaccination for SARS-CoV-2.

PMID:35334979 | DOI:10.3390/vaccines10030347

PLoS One. 2022 Mar 25;17(3):e0266083. doi: 10.1371/journal.pone.0266083. eCollection 2022.

ABSTRACT

BACKGROUND: Primary antibody deficiencies (PADs) without an identified monogenetic origin form the largest and most heterogeneous group of primary immunodeficiencies. These patients often remain undiagnosed for years and many present to medical attention in adulthood after several infections risking structural complications. Not much is known about their treatment, comorbidities, or prognosis, nor whether the various immunological forms (decreased total IgG, IgG subclass(es), IgM, IgA, specific antibody responses, alone or in combination(s)) should be considered as separate, clearly definable subgroups. The unclassified primary antibody deficiency (unPAD) study aims to describe in detail all PAD patients without an identified specific monogenetic defect regarding their demographical, clinical, and immunological characteristics at presentation and during follow-up. In constructing these patterns, the unPAD study aims to reduce the number of missed and unidentified PAD patients in the future. In addition, this study will focus on subclassifying unPAD to support the identification of patients at higher risk for infection or immune dysregulation related complications, enabling the development of personalized follow-up and treatment plans.

METHODS AND ANALYSIS: We present a protocol for a multicenter observational cohort study using the ESID online Registry. Patients of all ages who have given informed consent for participation in the ESID online Registry and fulfill the ESID Clinical Working Definitions for ‘unclassified antibody deficiency’, ‘deficiency of specific IgG’, ‘IgA with IgG subclass deficiency’, ‘isolated IgG subclass deficiency’, ‘selective IgM deficiency’, ‘selective IgA deficiency’ or ‘common variable immunodeficiency’ will be included. For all patients, basic characteristics can be registered at first registration and yearly thereafter in level 1 forms. Detailed characteristics of the patients can be registered in level 2 forms. Consecutive follow-up forms can be added indefinitely. To ensure the quality of the collected data, all data will be fully monitored before they are exported from the ESID online Registry for analysis. Outcomes will be the clinical and immunological characteristics of unPAD at presentation and during follow-up. Subgroup analyses will be made based on demographical, clinical and immunological characteristics.

PMID:35333892 | DOI:10.1371/journal.pone.0266083