“…In the immunological evaluation, T cell lymphopenia, low class‐switched B cells and reduced CTLA‐4 expression in memory T reg cells are detected; however, as opposed to CHAI and LATAIE, obvious T cell exhaustion is not usually present [33]. Another example is the presentation of the autoimmune lymphoproliferative syndrome (ALPS)‐like phenotype by LATAIE patients [26,34–36]. In this review, 22 (15.6%) LATAIE patients were initially diagnosed with ALPS.…”
Summary
Cytotoxic T lymphocyte antigen 4 (CTLA‐4) haploinsufficiency (CHAI) and lipopolysaccharide‐responsive beige‐like anchor (LRBA) deficiency (LATAIE) are newly identified inborn errors of immunity with shared molecular pathomechanisms and clinical manifestations. In this review, we aimed to provide differential comparisons regarding demographic, clinical, immunological and molecular characteristics between these two similar conditions. A literature search was conducted in PubMed, Web of Science and Scopus databases and included studies were systematically evaluated. Overall, 434 (222 CHAI and 212 LATAIE) patients were found in 101 eligible studies. The CHAI patients were mainly reported from North America and western Europe, while LATAIE patients were predominantly from Asian countries. In CHAI, positive familial history (P < 0·001) and in LATAIE, consanguineous parents (P < 0·001) were more common. In CHAI patients the rates of granulomas (P < 0·001), malignancies (P = 0·001), atopy (P = 0·001), cutaneous disorders (P < 0·001) and neurological (P = 0·002) disorders were higher, while LATAIE patients were more commonly complicated with life‐threatening infections (P = 0·002), pneumonia (P = 0·006), ear, nose and throat disorders (P < 0·001), organomegaly (P = 0·023), autoimmune enteropathy (P = 0·038) and growth failure (P < 0·001). Normal lymphocyte subsets and immunoglobulins except low serum levels of CD9+ B cells (14·0 versus 38·4%, P < 0·001), natural killer (NK) cells (21 versus 41·1%, P < 0·001), immunoglobulin (Ig)G (46·9 versus 41·1%, P = 0·291) and IgA (54·5 versus 44·7%, P = 0·076) were found in the majority of CHAI and LATAIE patients, respectively. The most frequent biological immunosuppressive agents prescribed for CHAI and LATAIE patients were rituximab and abatacept, respectively. Further investigations into the best conditioning and treatment regimens pre‐ and post‐transplantation are required to improve the survival rate of transplanted CHAI and LATAIE patients.
“…In the immunological evaluation, T cell lymphopenia, low class‐switched B cells and reduced CTLA‐4 expression in memory T reg cells are detected; however, as opposed to CHAI and LATAIE, obvious T cell exhaustion is not usually present [33]. Another example is the presentation of the autoimmune lymphoproliferative syndrome (ALPS)‐like phenotype by LATAIE patients [26,34–36]. In this review, 22 (15.6%) LATAIE patients were initially diagnosed with ALPS.…”
Summary
Cytotoxic T lymphocyte antigen 4 (CTLA‐4) haploinsufficiency (CHAI) and lipopolysaccharide‐responsive beige‐like anchor (LRBA) deficiency (LATAIE) are newly identified inborn errors of immunity with shared molecular pathomechanisms and clinical manifestations. In this review, we aimed to provide differential comparisons regarding demographic, clinical, immunological and molecular characteristics between these two similar conditions. A literature search was conducted in PubMed, Web of Science and Scopus databases and included studies were systematically evaluated. Overall, 434 (222 CHAI and 212 LATAIE) patients were found in 101 eligible studies. The CHAI patients were mainly reported from North America and western Europe, while LATAIE patients were predominantly from Asian countries. In CHAI, positive familial history (P < 0·001) and in LATAIE, consanguineous parents (P < 0·001) were more common. In CHAI patients the rates of granulomas (P < 0·001), malignancies (P = 0·001), atopy (P = 0·001), cutaneous disorders (P < 0·001) and neurological (P = 0·002) disorders were higher, while LATAIE patients were more commonly complicated with life‐threatening infections (P = 0·002), pneumonia (P = 0·006), ear, nose and throat disorders (P < 0·001), organomegaly (P = 0·023), autoimmune enteropathy (P = 0·038) and growth failure (P < 0·001). Normal lymphocyte subsets and immunoglobulins except low serum levels of CD9+ B cells (14·0 versus 38·4%, P < 0·001), natural killer (NK) cells (21 versus 41·1%, P < 0·001), immunoglobulin (Ig)G (46·9 versus 41·1%, P = 0·291) and IgA (54·5 versus 44·7%, P = 0·076) were found in the majority of CHAI and LATAIE patients, respectively. The most frequent biological immunosuppressive agents prescribed for CHAI and LATAIE patients were rituximab and abatacept, respectively. Further investigations into the best conditioning and treatment regimens pre‐ and post‐transplantation are required to improve the survival rate of transplanted CHAI and LATAIE patients.
“…We used some purified monoclonal antibodies that were not previously tested on FCM. In these experiments, careful titration was done, and test results were confirmed by targeted genetic analysis, until optimization of the FCM test was achieved [ 12 , 21 , 22 ].…”
Section: Methodsmentioning
confidence: 99%
“…Other immunological biomarkers that would help confirm the diagnosis included low B cells percentages and an increase in memory CD4+CD45RO+T cells (Fig. 5 ) [ 12 ]. Fig.…”
Section: Diagnosis Of Diseases Of Immune Dysregulationmentioning
Background
Human inborn errors of immunity (IEI) are a group of inherited genetic disorders of the immune system. IEI Patients suffer from severe repeated infections, autoimmunity, lymphadenopathy and/or increased susceptibility to malignancies. IEI are due to absence, disproportion, or loss of function of immune cells; mostly inherited in autosomal recessive manner, hence are more common in countries with high rate of consanguinity. Definite diagnosis of IEI is achieved by genetic analysis, however it is not always available. Aim: to report on different IEI categories and impact of expanding the use of flow cytometry (FCM) in diagnosis, categorization and follow up of IEI patients in a highly consanguineous population.
Methods
Retrospective chart review on different IEI categories diagnosed at the primary immunodeficiency center in Cairo University Specialized Pediatric hospital from 2011 to 2021 based on expanding the use of FCM.
Results
1510 IEI patients were diagnosed; 480 were diagnosed genetically with FMF, 11 with cystic fibrosis and 1019 patients were diagnosed with other IEI disorders. Phagocytic defects were the commonest (30%) followed by severe combined immunodeficiency (22%) and combined immunodeficiency (18.3%). FCM testing properly diagnosed and categorized 73% of the cases.
Conclusion
Using multi-color FCM to evaluate immune cells populations, subpopulations, functions, and intracellular proteins expression is proved a useful cost-effective method for screening, categorization and follow up of IEI patients. FCM can improve the diagnosis of IEI significantly when tests are properly targeted and well designed. This study presents a 10-year experience in diagnosis of IEI using FCM at a tertiary referral center in a setting of limited resources and yet high prevalence of IEI.
“…Although some immune cell frequencies are characteristic of a particular PID, for instance increased DNTs in ALPS, functional testing or screening tests based on mRNA or protein detection are currently being implemented for differential diagnosis or when the identified variant has not yet been reported as pathogenic. Specifically, the detection of LRBA protein by flow cytometry in either PHA-stimulated PBMCs or in unstimulated whole blood cells have been reported useful to discriminate with over 90% specificity and sensitivity LRBA-deficient patients harbouring LRBA biallelic mutations from LRBA-like patients with wild type LRBA sequence [ 71 , 72 ]. Although, the LRBA protein is found to be absent in most LRBA-deficient patients, the detection of it will not exclude LRBA deficiency as some patients present with normal or residual LRBA expression.…”
Section: Approaches For Differential Diagnosismentioning
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.
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