One of the causes of inborn errors of immunity is immune dysregulation. The inability of the immune system to regulate the extent of its activity has several deleterious effects, including ...autoimmunity, recurrent infections, and malignancy. In recent years, many proteins in the CD28 family – CD28, ICOS, CTLA‐4, PD‐1, and BTLA – have come into the focus of several research areas for their consequential role in the upregulation or downregulation of the immune response. In this review, we will discuss the structure and function of these proteins, as well as provide an overview of the clinical picture of patients with genetic defects.
The Arp2/3 complex drives the formation of branched actin networks that are essential for many cellular processes. In humans, the ARPC5 subunit of the Arp2/3 complex is encoded by two paralogous ...genes (ARPC5 and ARPC5L) with 67% identity. Through whole-exome sequencing, we identified a biallelic ARPC5 frameshift variant in a female child who presented with recurrent infections, multiple congenital anomalies, diarrhea, and thrombocytopenia, and suffered early demise from sepsis. Her consanguineous parents also had a previous child who died with similar clinical features. Using CRISPR/Cas9-mediated approaches, we demonstrate that loss of ARPC5 affects actin cytoskeleton organization and function in vitro. Homozygous Arpc5-/- mice do not survive past embryonic day 9 due to developmental defects, including loss of the second pharyngeal arch which contributes to craniofacial and heart development. Our results indicate that ARPC5 is important for both prenatal development and postnatal immune signaling, in a non-redundant manner with ARPC5L. Moreover, our observations add ARPC5 to the list of genes that should be considered when patients present with syndromic early-onset immunodeficiency, particularly if recessive inheritance is suspected.
Biallelic mutations in the human lipopolysaccharide responsive beige‐like anchor (LRBA) gene lead to a primary immunodeficiency known as LRBA deficiency, characterized by a broad range of clinical ...manifestations including autoimmunity, organomegaly, hypogammaglobulinemia and recurrent infections. Considering the phenotypic heterogeneity in patients and the severity of the disease, our aim was to assess the role of LRBA in immune cells and to understand the underlying pathomechanisms through the study of a Lrba knockout (Lrba−/−) mouse model. LRBA‐deficient mice did not show severe clinical or immunological signs of disease, either at steady state under specific‐pathogen‐free conditions, after vaccination with T‐dependent and T‐independent antigens, or in the context of acute infections with lymphocytic choriomeningitis virus (LCMV) or Salmonella Typhimurium. Although Lrba−/− mice were able to produce normal serum immunoglobulin M (IgM) and IgG and to mount a specific immune response after immunization, they showed elevated serum and secretory basal IgA levels. LRBA was dispensable for B‐ and T‐cell development, as well as for in vitro B‐cell proliferation, survival, isotype switching and plasmablast differentiation. Interestingly, Lrba−/− mice displayed decreased cytotoxic T‐lymphocyte‐associated protein‐4 (CTLA‐4) expression by regulatory T cells and activated conventional CD4+ and CD8+ T lymphocytes, reduced frequency of peritoneal B‐1a cells along with diminished interleukin‐10 production and increased percentages of T follicular helper cells in Peyer's patches, but without developing overt signs of autoimmunity. Our findings expand the role of LRBA in immune regulatory mechanisms previously reported in patients, and suggest a novel role in IgA production that is crucial for the protection of mucosal surfaces and gut‐associated immune tolerance.
Microalgae are complex photosynthetic organisms found in marine and freshwater environments that produce valuable metabolites. Microalgae-derived metabolites have gained remarkable attention in ...different industrial biotechnological processes and pharmaceutical and cosmetic industries due to their multiple properties, including antioxidant, anti-aging, anti-cancer, phycoimmunomodulatory, anti-inflammatory, and antimicrobial activities. These properties are recognized as promising components for state-of-the-art cosmetics and cosmeceutical formulations. Efforts are being made to develop natural, non-toxic, and environmentally friendly products that replace synthetic products. This review summarizes some potential cosmeceutical applications of microalgae-derived biomolecules, their mechanisms of action, and extraction methods.
The photolyase family consists of flavoproteins with enzyme activity able to repair ultraviolet light radiation damage by photoreactivation. DNA damage by the formation of a cyclobutane pyrimidine ...dimer (CPD) and a pyrimidine-pyrimidone (6-4) photoproduct can lead to multiple affections such as cellular apoptosis and mutagenesis that can evolve into skin cancer. The development of integrated applications to prevent the negative effects of prolonged sunlight exposure, usually during outdoor activities, is imperative. This study presents the functions, characteristics, and types of photolyases, their therapeutic and cosmetic applications, and additionally explores some photolyase-producing microorganisms and drug delivery systems.
The diagnosis of lipopolysaccharide-responsive beige-like-anchor-protein (LRBA) deficiency currently relies on gene sequencing approaches that do not support a timely diagnosis and clinical ...management. We developed a rapid and sensitive test for clinical implementation based on the detection of LRBA protein by flow cytometry in peripheral blood cells after stimulation. LRBA protein was assessed in a prospective cohort of 54 healthy donors and 57 patients suspected of LRBA deficiency. Receiver operating characteristics analysis suggested an LRBA:MFI ratio cutoff point of 2.6 to identify LRBA-deficient patients by FACS with 94% sensitivity and 80% specificity and to discriminate them from patients with a similar clinical picture but other disease-causing mutations. This easy flow cytometry-based assay allows a fast screening of patients with suspicion of LRBA deficiency reducing therefore the number of patients requiring LRBA sequencing and accelerating the treatment implementation. Detection of biallelic mutations in
is however required for a definitive diagnosis.
Autoimmune lymphoproliferative syndrome (ALPS) is an inherited non-malignant and non-infectious lymphoproliferative syndrome caused by mutations in genes affecting the extrinsic apoptotic pathway ...(FAS, FASL, CASP10). The resulting FAS-mediated apoptosis defect accounts for the expansion and accumulation of autoreactive (double-negative) T cells leading to cytopenias, splenomegaly, lymphadenopathy, autoimmune disorders, and risk of lymphoma. However, there are other monogenetic disorders known as ALPS-like syndromes that can be clinically similar to ALPS but are genetically and biologically different, such as observed in patients with immune checkpoint deficiencies, particularly cytotoxic T-lymphocyte antigen 4 (CTLA-4) insufficiency and lipopolysaccharide-responsive beige-like anchor protein LRBA deficiency. CTLA-4 insufficiency is caused by heterozygous mutations in CTLA-4, an essential negative immune regulator that is constitutively expressed on regulatory T (Treg) cells. Mutations in CTLA-4 affect CTLA-4 binding to CD80-CD86 costimulatory molecules, CTLA-4 homodimerization, or CTLA-4 intracellular vesicle trafficking upon cell activation. Abnormal CTLA-4 trafficking is also observed in patients with LRBA deficiency, a syndrome caused by biallelic mutations in LRBA that abolishes the LRBA protein expression. Both immune checkpoint deficiencies are biologically characterized by low levels of CTLA-4 protein on the cell surface of Tregs, accounting for the autoimmune manifestations observed in CTLA4-insufficient and LRBA-deficient patients. In addition, both immune checkpoint deficiencies present with an overlapping but heterogeneous clinical picture despite the difference in inheritance and penetrance. In this review, we describe the most prominent clinical features of ALPS, CTLA-4 insufficiency and LRBA deficiency, emphasizing their corresponding biological mechanisms. We also provide some clinical and laboratory approaches to diagnose these three rare immune disorders, together with therapeutic strategies that have worked best at improving prognosis and quality life of patients.
Background LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency caused by biallelic mutations in LRBA that abolish LRBA protein expression. Objective We sought to ...report the extended phenotype of LRBA deficiency in a cohort of 22 LRBA-deficient patients. Methods Clinical criteria, protein detection, and genetic sequencing were applied to diagnose LRBA deficiency. Results Ninety-three patients met the inclusion criteria and were considered to have possible LRBA deficiency. Twenty-four patients did not express LRBA protein and were labeled as having probable LRBA deficiency, whereas 22 were genetically confirmed as having definitive LRBA deficiency, with biallelic mutations in LRBA . Seventeen of these were novel and included homozygous or compound heterozygous mutations. Immune dysregulation (95%), organomegaly (86%), recurrent infections (71%), and hypogammaglobulinemia (57%) were the main clinical complications observed in LRBA-deficient patients. Although 81% of LRBA-deficient patients had normal T-cell counts, 73% had reduced regulatory T (Treg) cell numbers. Most LRBA-deficient patients had low B-cell subset counts, mainly in switched memory B cells (80%) and plasmablasts (92%), with a defective specific antibody response in 67%. Of the 22 patients, 3 are deceased, 2 were treated successfully with hematopoietic stem cell transplantation, 7 are receiving immunoglobulin replacement, and 15 are receiving immunosuppressive treatment with systemic corticosteroids alone or in combination with steroid-sparing agents. Conclusion This report describes the largest cohort of patients with LRBA deficiency and offers guidelines for physicians to identify LRBA deficiency, supporting appropriate clinical management.
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