Algerian Registry for Inborn Errors of Immunity in Children: Report of 887 Children (1985-2021).

INTRODUCTION: Inborn errors of immunity (IEI) represent a heterogeneous large group of genetic disorders characterized by susceptibility of affected individuals to recurrent infections, autoimmune/inflammatory diseases, allergy, and malignancy. We aimed to report for the first time the Algerian registry for IEI in children. METHODS: We described the characteristics of IEI in Algerian children from the data collected in the Algerian registry for IEI between 1985 and 2021. RESULTS: Over a period of 37 years, we included 887 children (530 male, 59.6%) with a mean age at diagnosis of 3.23 years and a mean diagnosis delay of 2 years. The prevalence rate was estimated at 1.97/100,000 inhabitants or 5.91/100,000 children. The parental consanguinity was found in 52.6%. The most prevalent category was combined immunodeficiencies (CID) (35.5%), followed by predominantly antibody deficiencies (24.5%) and CID with syndromic features (18.3%). The most predominant diseases were severe CID (134 cases), MHC II deficiency (99 cases), agammaglobulinemia (82 cases), common variable immunodeficiency (78 cases), hyper IgE syndromes (61 patients), ataxia-telangiectasia (46 patients), Wiskott-Aldrich syndrome (40 patients) and chronic granulomatous disease (39 cases). The clinical presentation was dominated by lower respiratory tract infections (69%), failure to thrive (38.3%), and chronic diarrhea (35.2%). Genetic analysis was performed in 156 patients (17.6%). The global mortality rate was 28.4% mainly caused by CID. CONCLUSION: This is the first report of the Algerian registry for IEI in children. Data is globally similar to that of the Middle East and North African (MENA) registries with high consanguinity, predominance of CID, and significant mortality. This registry highlights the weak points that should be improved in order to provide better patient care.

Auto-immunity profile evaluation during different clinical manifestations of Behçet disease in Algerian patients: effect of corticosteroid treatment.

BACKGROUND AND AIMS: Behçet disease (BD) is a chronic multisystem disease. It stands at the crossroads between the auto-immunity and auto-inflammatory disorders. Our study aims to evaluate corticosteroids therapy effects on serum immunoglobulin isotypes and anti-phospholipid auto-anti-body production in Algerian BD patients with different clinical manifestations. METHODS: We evaluated serum immunoglobulin isotypes and anti-phospholipid (anti-cardiolipin, anti-ß2glycoprotein I, anti-prothrombin) auto-anti-body production using Turbidimetric or Luminex platform assays. Our study was conducted in naïve active BD patients and in corticosteroid-treated patients with different clinical manifestations. RESULTS AND DISCUSSION: Our results indicate that IgM, IgG, and IgA levels were higher in naïve active patients. The increase in sera isotypes did not differ according to the clinical manifestation, except for IgA production, which was associated with an increased risk of mucocutaneous and ocular involvement. Interestingly, in corticosteroid-treated active patients, no difference was reported between each clinical subgroup. Furthermore,anti-cardiolipin, anti-ß2glycoprotein I and anti-prothrombin auto-anti-body levels were elevated in naïve active patients. Contrary to anti-prothrombin, high anti-cardiolipin and anti-ß2glycoprotein I, production differed according to the clinical manifestations and was associated with an increased risk of mucocutaneous and ocular involvement. Importantly, corticosteroid therapy significantly reduced these immune markers regardless of the clinical manifestations. CONCLUSION: Our results suggest that high IgA production could be a risk marker of uveitis in naïve active patients. Moreover, concomitant high anti-cardiolipin, anti-ß2glycoprotein I and anti-prothrombin production is related to an increased risk of mucocutaneous lesions, ocular and vascular involvement. Collectively, our data indicate the importance of evaluating the corticosteroid effect on immune responses associated with BD to ensure an adequate investigation of each related clinical manifestation.

Serum Free Light Chain Predict Overall Survival and Response to Therapy in Patients with Newly Diagnosed Multiple Myeloma.

BACKGROUND: Multiple myeloma is characterized by underlying clinical and biological heterogeneity, which translates to variable responses to treatment and outcome. METHODS: To assess the roles of serum free light chain (sFLC) and K/L FLC ratio (rFLC) in the diagnoses and prognoses of multiple myeloma (MM), sFLC levels and K/L ratios were measured in 112 patients with newly diagnosed multiple myeloma using the Freelite automated immunoassay. RESULTS: Abnormal sFLC and/or rFLC levels were detected 99.1% of the patients. The baseline sFLC predicted the overall survival (OS). The median OSs were not reached (NR) and were 30 months in the low sFLC group (sFLC-K < 132 mg/L or sFLC-L < 342 mg/L) and the high sFLC group (sFLC-K ≥ 132 mg/L or sFLC-L ≥ 342 mg/ L) (p < 0.001), respectively. Similarly, the rFLC successfully predicted the OS times of 29 months for group A (rFLC ≤ 0.03 or ≥ 32) and NR for group B (0.03 < rFLC < 32) (p < 0.001). According to the response to treatment and sFLC ratio, significant differences in the OSs were observed between the partial response group and other patients, (respectively, OS median = 28 months vs. NR, log rank p < 0.001). Additionally, the patients were further stratified into two groups using the novel poor-prognosis factors (rFLC > 32 or < 0.03) combined with the International Staging System parameters (beta2-microglobulin, albumin), i.e., a low-risk group (those with zero or one factor) and a high-risk group (those with two or three factors). The median OSs for the low- and high-risk groups were NR and 29 months, respectively (p = 0.001). CONCLUSIONS: The sFLC assay was extremely sensitive in the diagnosis of MM. In addition to its strong prognosis value, it could be a predictor of response to therapy.

Influence of corticosteroid therapy on IL-18 and nitric oxide production during Behçet's disease.

BACKGROUND AND AIMS: Behçet's disease (BD) is a chronic multisystemic inflammatory disease with complex etiopathogenesis. Th1-proinflammatory cytokines seem to be involved in its pathogenesis. Our current study aims to evaluate interleukin-18 (IL-18) and nitric oxide (NO) involvement in the development of different clinical manifestations of BD as well as to investigate the corticosteroid therapy effect on this production in Algerian patients. METHODS: For this purpose, we evaluated in vivo and ex vivo IL-18, interferon-γ (IFN-γ) levels using ELISA and NO production by the Griess' method in naïve-active and corticosteroid-treated BD patients with different clinical manifestations. Additionally, we assessed CD40/CD40L expression by flow cytometrics assay in these groups of patients. RESULTS AND DISCUSSION: Our results indicate that IL-18 and nitrite levels were higher in naïve-active BD patients. Interestingly, this high production differed according to the clinical manifestations and was associated with an increased risk of mucocutaneous and vascular involvement. Concerning corticosteroid treated-active BD patients, no difference was observed in this production between each clinical subgroup. However, IFN-γ levels increased in all categories of active patients. Interestingly, corticosteroid therapy reduced significantly these inflammatory mediators regardless of the clinical manifestations studied. In addition, the CD40/CD40L expression differed according to the clinical presentations. CONCLUSION: Collectively, our results suggest that concomitant high production of IL-18 and NO in naïve-active BD patients is related to an increased risk of mucocutaneous lesions and vascular involvement. Moreover, the relationship between these two inflammatory markers could constitute a predictable tool of BD clinical presentations and an early factor of therapy efficiency.

Prevalence of BTK mutations in male Algerian patterns with agammaglobulinemia and severe B cell lymphopenia.

X linked agammaglobulinemia (XLA) is the first described primary immunodeficiency and the most common form of agammaglobulinemia. It is characterized by susceptibility to recurrent infections, profound decrease of all immunoglobulin isotypes and very low level of B lymphocytes in peripheral blood. The disorder is caused by mutations in the Bruton's Tyrosine Kinase (BTK). Nine male patients suspected to have XLA from nine unrelated families were enrolled in this study. We performed sequencing of the BTK gene in all nine patients, and in the patients' relatives when possible. The XLA diagnosis was confirmed for six patients with six different mutations; we identified a novel mutation (c.1522G>A) and five known mutations. One third of nine unrelated patients do not have mutations in BTK and thus likely suffer from autosomal recessive agammaglobulinemia in the setting of consanguinity. Our results support that the autosomal recessive agammaglobulinemia can be more common in Algeria.

Clinical, immunological and genetic features in eleven Algerian patients with major histocompatibility complex class II expression deficiency.

Presenting processed antigens to CD4+ lymphocytes during the immune response involves major histocompatibility complex class II molecules. MHC class II genes transcription is regulated by four transcription factors: CIITA, RFXANK, RFX5 and RFXAP. Defects in these factors result in major histocompatibility complex class II expression deficiency, a primary combined immunodeficiency frequent in North Africa. Autosomal recessive mutations in the RFXANK gene have been reported as being the principal defect found in North African patients with this disorder. In this paper, we describe clinical, immunological and genetic features of 11 unrelated Algerian patients whose monocytes display a total absence of MHC class II molecules. They shared mainly the same clinical picture which included protracted diarrhoea and respiratory tract recurrent infections. Genetic analysis revealed that 9 of the 11 patients had the same RFXANK founder mutation, a 26 bp deletion (named I5E6-25_I5E6+1, also known as 752delG26). Immunological and genetic findings in our series may facilitate genetic counselling implementation for Algerian consanguineous families. Further studies need to be conducted to determine 752delG26 heterozygous mutation frequency in Algerian population.

Association study of human leukocyte antigen-DRB1 alleles with rheumatoid arthritis in Algerian patients.

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory and multifactorial disease. Genetic predisposition seems to play an important role. The aim of this study is to explore the relationship between human leukocyte antigen (HLA)-DRB1 alleles and susceptibility, clinical and biological features of RA in an Algerian patient population. METHODS: Using polymerase chain reaction - sequence specific primers (SSP), 134 RA patients and 132 healthy controls were genotyped for HLA-DRB1 and HLA-DRB1*04 subtypes. RESULTS: HLA-DRB1*04 was found to have increased frequency in the RA group compared to controls (P < 0.001, OR = 3.14), and was associated with anti-citrullinated protein antibodies positivity (ACPA) (P = 0.01, OR = 2.35). In contrast, HLA-DRB1*07 was found to have a decreased frequency in patients compared to controls (P = 0.003, OR = 0.44) and significant decrease was observed in patients with the rheumatoid factor (RF) positivity subgroup (P = 0.009, OR = 0.29). HLA-DRB1*04:05 was associated with RA (P = 0.005, OR = 3.41), whereas, HLA-DRB1*04:02 showed a protective effect against RA (P = 0.003, OR = 0.20). CONCLUSIONS: HLA-DRB1*04 was associated with increased risk for RA and ACPA positivity, while HLA-DRB1*07 was associated with reduced risk for RA and RF synthesis in Algerian patients.

T cells activation and interferon-γ/nitric oxide production during Behçet disease: a study in Algerian patients.

The aim of the current study is to situate CDs expression (CD3+, CD4+, CD8+) and their relationship with IFNγ and NO production in Algerian patients with Behçet disease (n = 34 ). Our results revealed an elevated expression of T cells markers tested in patients in active stage of the disease in relation to IFNγ and NO increase levels. Most interestingly, we noted that CD4+/CD8+ expression correlated with IFNγ and NO production in active stage. In contrast, we observed a decrease of these mediators in inactive stage. Collectively, our results indicate a dependent relation between these parameters and inflammatory response associated with the evolutionary stage of the disease.