A low-activity variant of endoplasmic reticulum aminopeptidase 1 (ERAP1), Hap10, is associated with the autoinflammatory disorder Behçet's disease (BD) in epistasis with HLA-B*51, which is the main ...risk factor for this disorder. The role of Hap10 in BD pathogenesis is unknown. We sought to define the effects of Hap10 on the HLA-B*51 peptidome and to distinguish these effects from those due to HLA-B*51 polymorphisms unrelated to disease. The peptidome of the BD-associated HLA-B*51:08 subtype expressed in a Hap10-positive cell line was isolated, characterized by mass spectrometry, and compared with the HLA-B*51:01 peptidome from cells expressing more active ERAP1 allotypes. We additionally performed synthetic peptide digestions with recombinant ERAP1 variants and estimated peptide-binding affinity with standard algorithms. In the BD-associated ERAP1 context of B*51:08, longer peptides were generated; of the two major HLA-B*51 subpeptidomes with Pro-2 and Ala-2, the former one was significantly reduced, and the latter was increased and showed more ERAP1-susceptible N-terminal residues. These effects were readily explained by the low activity of Hap10 and the differential susceptibility of X–Pro and X–Ala bonds to ERAP1 trimming and together resulted in a significantly altered peptidome with lower affinity. The differences due to ERAP1 were clearly distinguished from those due to HLA-B*51 subtype polymorphism, which affected residue frequencies at internal positions of the peptide ligands. The alterations in the nature and affinity of HLA-B*51·peptide complexes probably affect T-cell and natural killer cell recognition, providing a sound basis for the joint association of ERAP1 and HLA-B*51 with BD.
Patients with immune-mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis and inflammatory bowel disease, are at increased risk of infection. International guidelines recommend ...vaccination to limit this risk of infection, although live attenuated vaccines are contraindicated once immunosuppressive therapy has begun. Biologic therapies used to treat IMIDs target the immune system to stop chronic pathogenic process but may also attenuate the protective immune response to vaccines. Here, we review the current knowledge regarding vaccine responses in IMID patients receiving treatment with biologic therapies, with a focus on the interleukin (IL)-12/23 inhibitors. B cell-depleting therapies, such as rituximab, strongly impair vaccines immunogenicity, and tumor necrosis factor (TNF) inhibitors and the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) fusion protein abatacept are also associated with attenuated antibody responses, which are further diminished in patients taking concomitant immunosuppressants. On the other hand, integrin, IL-6, IL-12/23, IL-17, and B-cell activating factor (BAFF) inhibitors do not appear to affect the immune response to several vaccines evaluated. Importantly, treatment with biologic therapies in IMID patients is not associated with an increased risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or developing severe disease. However, the efficacy of SARS-CoV-2 vaccines on IMID patients may be reduced compared with healthy individuals. The impact of biologic therapies on the response to SARS-CoV-2 vaccines seems to replicate what has been described for other vaccines. SARS-CoV-2 vaccination appears to be safe and well tolerated in IMID patients. Attenuated but, in general, still protective responses to SARS-CoV-2 vaccination in the context of certain therapies warrant current recommendations for a third primary dose in IMID patients treated with immunosuppressive drugs.
Schimke immuno-osseous dysplasia (SIOD) caused by mutations in
is an ultra-rare disease characterized by specific facial features, skeletal dysplasia, and steroid-resistant nephrotic syndrome, which ...often leads to kidney failure and requires transplantation. Cellular (T-cell) deficiency, lymphopenia, and infections have been frequently reported, but whether they are due to T-cell-intrinsic defects in T-cell receptor (TCR) signaling associated with SMARCAL1 deficiency or to T-cell-extrinsic effects such as the impaired proliferation of hematopoietic precursors or T-cell-specific immunosuppression after renal transplantation remains unknown. We have explored the effects of SMARCAL1 deficiency on T-cell receptor signaling in primary and immortalized T cells from a 9-year-old SIOD patient under immunosuppression treatment when compared to healthy donors. Immortalized T cells recapitulated the SMARCAL1 deficiency of the patient, as judged by their impaired response to gamma irradiation. The results indicated that TCR-mediated signaling was normal in SIOD-derived immortalized T cells but strongly impaired in the primary T cells of the patient, although rescued with TCR-independent stimuli such as PMA + ionomycin, suggesting that SIOD-associated T-cell signaling is not intrinsically defective but rather the result of the impaired proliferation of hematopoietic precursors or of T-cell-specific immunosuppression. The lack of early thymic emigrants in our patients may support the former hypothesis.
Complement as a diagnostic tool in immunopathology López-Lera, Alberto; Corvillo, Fernando; Nozal, Pilar ...
Seminars in cell & developmental biology,
January 2019, 2019-01-00, 20190101, Volume:
85
Journal Article
Peer reviewed
Open access
The complement system is a complex and autoregulated multistep cascade at the interface of innate and adaptive immunity. It is activated by immune complexes or apoptotic cells (classical pathway), ...pathogen-associated glycoproteins (lectin pathway) or a variety of molecular and cellular surfaces (alternative pathway). Upon activation, complement triggers the generation of proteolytic fragments that allow the elimination of the activating surface by enhancing inflammation, opsonization, phagocytosis, and cellular lysis. Moreover, complement efficiently discriminates self from non-self surfaces by means of soluble and membrane-bound complement regulators which are critical for innate self-tolerance. Complement deficiency or dysfunction disturb complement homeostasis and give rise to diseases as diverse as bacterial infections, autoimmunity, or renal and neurological disorders. Research on complement-targeted therapies is an expanding field that has already improved the prognosis of severe diseases such as atypical Haemolytic Uremic syndrome or Paroxysmal Nocturnal Haemoglobinuria. Therefore, complement analysis and monitoring provides valuable information with deep implications for diagnosis and therapy. In addition to its important role as an extracellular defense system, it has now become evident that complement is also present intracellularly, and its activation has profound implications for leukocyte survival and function. In this review, we summarize the essential, up-to-date information on the use of complement as a diagnostic and therapeutic tool in the clinics.
Inherited human ezrin deficiency impairs adaptive immunity García-Solís, Blanca; Van Den Rym, Ana; Martinez-Martínez, Laura ...
Journal of allergy and clinical immunology,
October 2023, 2023-10-00, 20231001, Volume:
152, Issue:
4
Journal Article
Peer reviewed
Open access
Inborn errors of immunity (IEI) are a group of monogenic diseases that confer susceptibility to infection, autoimmunity, and cancer. Despite the life-threatening consequences of some IEI, their ...genetic cause remains unknown in many patients.
We investigated a patient with an IEI of unknown genetic etiology.
Whole-exome sequencing identified a homozygous missense mutation of the gene encoding ezrin (EZR), substituting a threonine for an alanine at position 129.
Ezrin is one of the subunits of the ezrin, radixin, and moesin (ERM) complex. The ERM complex links the plasma membrane to the cytoskeleton and is crucial for the assembly of an efficient immune response. The A129T mutation abolishes basal phosphorylation and decreases calcium signaling, leading to complete loss of function. Consistent with the pleiotropic function of ezrin in myriad immune cells, multidimensional immunophenotyping by mass and flow cytometry revealed that in addition to hypogammaglobulinemia, the patient had low frequencies of switched memory B cells, CD4+ and CD8+ T cells, MAIT, γδ T cells, and centralnaive CD4+ cells.
Autosomal-recessive human ezrin deficiency is a newly recognized genetic cause of B-cell deficiency affecting cellular and humoral immunity.
Complement in leucocyte development and function Regueiro, José R.; Fernández, Francisco J.; Vega, M. Cristina
Seminars in cell & developmental biology,
January 2019, 2019-01-00, 20190101, Volume:
85
Journal Article
Complement in basic processes of the cell Jiménez-Reinoso, Anaïs; Marin, Ana V.; Regueiro, José R.
Molecular immunology,
April 2017, 2017-04-00, 20170401, Volume:
84
Journal Article
Peer reviewed
•Extrahepatic and autocrine complement influence their local behavior.•Complotypes can tilt complement activation toward inflammation.•Extracellular complement regulates dendritic cell ...differentiation.•Extracellular complement regulates B cell function through CR and TLR crosstalk.•Intracellular C3 and C5 cleavage have crucial autocrine roles in T-cell function.
The complement system is reemerging in the last few years not only as key element of innate immunity against pathogens, but also as a main regulator of local adaptive responses, affecting dendritic cells as well as T and B lymphocytes. We review data showing that leucocytes are capable of significant autocrine synthesis of complement proteins, and express a large range of complement receptors, which in turn regulate their differentiation and effector functions while cross talking with other innate receptors such as Toll-like receptors. Other unconventional roles of complement proteins are reviewed, including their impact in non-leukocytes and their intracellular cleavage by vesicular proteases, which generate critical cues required for T cell function. Thus, leucocytes are very much aware of complement-derived information, both extracellular and intracellular, to elaborate their responses, offering rich avenues for therapeutic intervention and new hypothesis for conserved major histocompatibility complex complotypes.
...we generated pure T- and B-cell lines from our cohort and analyzed their intracellular C3 content by flow cytometry using specific mAb against 2 C3-associated neoepitopes (see Fig E4 in this ...article's Online Repository at www.jacionline.org). Analysis and gating strategy for CD8+ T-cell subsets was performed as previously described.E4,E5 Proliferation in response to mitogens and antibody titers PBMCs were stained with carboxyfluorescein succinimidyl ester (from Molecular Probes, Eugene, Ore) and cultured in RPMI-1640 supplemented with 10% FBS for 5 days after stimulation with 1 μg/mL plate-coated anti-CD3 (UCHT-1, OKT3; eBioscience, Waltham, Mass), 5 μg/mL Phaseolus vulgaris leucoagglutinin (PHA), 10 ng/mL phorbol 12-myristate 13-acetate and 1 μM ionomycin, 8 μg/mL Phytolacca americana pokeweed mitogen (PWM) (Sigma-Aldrich, St Louis, Mo), or 10 ng/mL superantigens (Staphylococcal Enterotoxin B or E; Toxin Technology, Inc, Sarasota, Fla). Generation of transformed T- and B-cell lines Human T-cell lymphotropic virus type 1-transformed T-cell lines, which have been reported to synthesize higher intracellular C3 than resting or activated primary T cells,E7 were generated as reported,E8 and maintained in RMPI-1640 supplemented with 10% FBS, 1% l-glutamine, 1% Antibiotic-Antimycotic (Gibco, Waltham, Mass), and 100 IU/mL recombinant human IL-2 (provided by Craig W. Reynolds, Frederick Cancer Research and Development Center, National Cancer Institute, National Institutes of Health, Frederick, Md). Code Plasma C3 deficiency Age (y) Main renal pathology Renal dysfunction stage‡ Other pathologies Infections§ Current condition % Memory B cells|| AD∗ PA† Unswitched Switched C3.1.II:1 Primary 9 18 MPGN I 1 HSPArthralgia Pneumonia (x2) Normal renal functionMild proteinuria 2.40 1.70 C3.2.II:1 Primary 1 13 MPGN I 1 HSPHemolytic anemiaChronic hemolysisSplenomegaly Streptoccocal pharingytisViral meningitis, B19 parvovirus Normal renal functionChronic hemolysisSplenomegaly 8.70 6.50 C3.3.II:2 Secondary 23 40 C3G 3 HSPHypertensionHypercholesterolemia SepticemiaPneumonia ProteinuriaMild hematuria 8.40 7.90 C3.4.I:1 Secondary 45 49 - 1 - - Asymptomatic 6.54 22.40 CFI.1.II.1 Secondary 23 39 - - - Meningococcal septicemiaMeningococcal meningitis Asymptomatic 4.20 3.90 CFI.1.II.4 Secondary 14 30 - - - Meningitis Asymptomatic 3.70 4.70 CFI.2.II:2 Secondary 19 53 - - HSPChronic juvenile arthritis Meningococcal meningitisPneumococcal pneumonia Asymptomatic 5.67 12.88 1 E.S. Reis, D.A. Falcão, L. Isaac, Clinical aspects and molecular basis of primary deficiencies of complement component C3 and its regulatory proteins factor I and factor H, Scand J Immunol, Vol. 63, 2006, 155-168 2 A.K. Matsumoto, D.R. Martin, R.H. Carter, L.B. Klickstein, J.M. Ahearn, D.T. Fearon, J Exp Med, Vol. 178, 1993, 1407-1417 3 P.W. Dempsey, M.E. Allison, S. Akkaraju, C.C. Goodnow, D.T. Fearon, C3d of complement as a molecular adjuvant: bridging innate and acquired immunity, Science, Vol. 271, 1996, 348-350 4 A. Ghannam, M. Pernollet, J.L. Fauquert, N. Monnier, D. Ponard, M.B. Villiers, Human C3 deficiency associated with impairments in dendritic cell differentiation, memory B cells, and regulatory T cells, J Immunol, Vol. 181, 2008, 5158-5166 5 Y. Okura, I. Kobayashi, M. Yamada, S. Sasaki, Y. Yamada, I. Kamioka, Clinical characteristics and genotype-phenotype correlations in C3 deficiency, J Allergy Clin Immunol, Vol. 137, 2016, 640-644.e1 6 M.K. Liszewski, M. Kolev, G. Le Friec, M. Leung, P.G. Bertram, A.F. Fara, Intracellular complement activation sustains T cell homeostasis and mediates effector differentiation, Immunity, Vol. 39, 2013, 1143-1157 7 C. Théry, M. Ostrowski, E. Segura, Membrane vesicles as conveyors of immune responses, Nat Rev Immunol, Vol. 9, 2009, 581-593 8 C. Hess, C. Kemper, Complement-mediated regulation of metabolism and basic cellular processes, Immunity, Vol. 45, 2016, 240-254
The outbreak of the novel coronavirus SARS-CoV-2 epidemic has rapidly spread and still poses a serious threat to healthcare systems worldwide. In the present study, electronic medical records ...containing clinical indicators related to liver injury in 799 COVID-19-confirmed patients admitted to a hospital in Madrid (Spain) were extracted and analyzed. Correlation between liver injury and disease outcome was also evaluated. Serum levels of Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Gamma-glutamyltransferase (GGT), Alkaline phosphatase (ALP), Lactate dehydrogenase (LDH) and AST/ALT ratio were elevated above the Upper Limit of Normal (ULN) in 25.73%, 49.17%, 34.62%, 24.21%, 55.84% and 75% of patients, respectively. Interestingly, significant positive correlation between LDH levels and the AST/ALT ratio with disease outcome was found. Our data showed that SARS-CoV-2 virus infection leads to mild, but significant changes in serum markers of liver injury. The upregulated LDH levels as well as AST/ALT ratios upon admission may be used as additional diagnostic characteristic for COVID-19 patients.
Mutations in T-cell antigen receptor (TCR) subunit genes cause rare immunodeficiency diseases characterized by impaired expression of the TCR at the cell surface and selective T lymphopenia. Here, ...detailed analyses of spontaneously arising somatic mutations that recover CD247, and thus TCR expression, in a newly identified CD247-deficient patient are described. The recovery of CD247 expression in some patient T cells was associated with both reversion of the inactivating mutation and a variant with a compensating mutation that could reconstitute TCR expression, but not as efficiently as wild-type CD247. Multiple mutations were found in CD247 complementary DNAs (cDNAs) cloned from the patient as well as in cDNA and genomic DNA from other individuals, suggesting that genetic variation in this gene is frequent. Analyses of other genes mutated in primary immunodeficiency diseases (PIDs) where reversions have been described also revealed a higher rate of mutation than that observed for genes mutated in PIDs where revertants have not been identified or control genes. These data support the hypothesis that the occurrence of somatic mutations that may reconstitute genetic defects in PID is related to an increased propensity of those genes to mutate.
•The propensity of genes to mutate influences the probability of spontaneous reversion of genetic defects in PID.
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