Consanguineous marriages in Middle Eastern and North African (MENA) countries are deeply-rooted tradition and highly prevalent resulting into increased prevalence of autosomal recessive diseases ...including Inborn Errors of Immunity (IEIs). Molecular genetic testing is an important diagnostic tool for IEIs since it provides a definite diagnosis, genotype-phenotype correlation, and guide therapy. In this review, we will discuss the current state and challenges of genomic and variome studies in MENA region populations, as well as the importance of funding advanced genome projects. In addition, we will review the MENA underlying molecular genetic defects of over 2457 patients published with the common IEIs, where autosomal recessive mode of inheritance accounts for 76% of cases with increased prevalence of combined immunodeficiency diseases (50%). The efforts made in the last three decades in terms of international collaboration and of in situ capacity building in MENA region countries led to the discovery of more than 150 novel genes involved in IEIs. Expanding sequencing studies within the MENA will undoubtedly be a unique asset for the IEI genetics which can advance research, and support precise genomic diagnostics and therapeutics.
•Consanguineous marriages in MENA are prevalent resulting into increased prevalence of autosomal recessive Inborn Errors of Immunity (IEIs).•At least 150 novel IEIs have been discovered through collaborative research from MENA paving the way to improve our knowledge on immune pathways.•More than 2500 patients reported shed light into common underlying genetic defects for IEIs in MENA.•Capacity-building in genetic diagnostic services and genetic counseling expertise that respects common values and cultures is needed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Tuberculosis, a human infectious disease caused by
(
), is still a major cause of morbidity and mortality worldwide. The success of
as a pathogen relies mainly on its ability to divert the host ...innate immune responses. One way by which
maintains a persistent infection in a "silent" granuloma is to inhibit inflammation and induce an immunoregulatory phenotype in host macrophages (MΦs). However,
effectors governing the switch of MΦs from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype remain to be determined. The
arly
ecreted
ntigenic
arget 6 kDa or ESAT-6, has been implicated in the virulence and pathogenesis of tuberculosis. Here, we investigated roles of ESAT-6 in MΦ differentiation and polarization. We found that treatment of human monocytes with ESAT-6 did not interfere with differentiation of M1 MΦs. However, ESAT-6 promoted differentiation of M0 and M2 MΦs toward the M1 phenotype, as indicated by secretion of pro-inflammatory cytokines IL-6, IL-12, and TNF-α, and induction of a typical M1 transcriptional signature. Interestingly, we found that ESAT-6 switched terminal full activation of M1 polarized MΦs to the M2 phenotype. Indeed, in the pro-inflammatory M1 MΦs, ESAT-6 was able to inhibit IL-12 and TNF-α secretion and stimulate that of IL-10. Moreover, gene expression profiling of these cells showed that ESAT-6 induced downregulation of M1 MΦ cell surface molecules
and
, transcription factors
and
, cytokines
, and
, as well as chemokines
and
. Overall, our findings suggest ESAT-6 as being one of the effectors used by
to induce the pro-inflammatory M1 phenotype at the primo-infection; a prerequisite step to promote granuloma formation and subsequently drive the phenotype switch of MΦ polarization from M1 to M2 at a later stage of the infection. Our study improves current knowledge regarding mechanisms of virulence of
and may be helpful to develop novel tools targeting ESAT-6 for a better and more efficient treatment of tuberculosis.
Background
The specificities of IgE and IgG for allergen molecules in patients with inborn errors of immunity (IEI) have not been investigated in detail.
Objective
To study IgE and IgG antibody ...specificities in patients with defined hyper‐IgE syndromes (HIES) using a comprehensive panel of allergen molecules.
Methods
We used chips containing micro‐arrayed allergen molecules to analyze allergen‐specific IgE and IgG levels in sera from two groups of HIES patients: Autosomal recessive mutations in phosphoglucomutase‐3 (PGM3); Autosomal dominant negative mutations of STAT3 (STAT3); and age‐matched subjects with allergic sensitizations. Assays with rat basophil leukemia cells transfected with human FcεRI were performed to study the biological relevance of IgE sensitizations.
Results
Median total IgE levels were significantly lower in the sensitized control group (212.9 kU/L) as compared to PGM3 (5042 kU/L) and STAT3 patients (2561 kU/L). However, PGM3 patients had significantly higher allergen‐specific IgE levels and were sensitized to a larger number of allergen molecules as compared to STAT3 patients. Biological relevance of IgE sensitization was confirmed for PGM3 patients by basophil activation testing. PGM3 patients showed significantly lower cumulative allergen‐specific IgG responses in particular to milk and egg allergens as compared to STAT3 patients and sensitized controls whereas total IgG levels were comparable to STAT3 patients and significantly higher than in controls.
Conclusion
The analysis with multiple micro‐arrayed allergen molecules reveals profound differences of allergen‐specific IgE and IgG recognition in PGM3 and STAT3 patients which may be useful for classification of IEI and clinical characterization of patients.
This study assesses IgE and IgG antibody specificities in HIES patients using a comprehensive panel of allergen molecules. Median total IgE levels are significantly lower in the sensitized control group as compared to PGM3 and STAT3 patients. PGM3 patients have significantly higher allergen‐specific IgE levels and are sensitized to a larger number of allergen molecules as compared to STAT3 patients.Abbreviations: IEI, inborn errors of immunity; ISU, ISAC standardized unit; HIES, hyper‐IgE syndrome; kU/L, kilo unit per liter; PGM3, autosomal‐recessive phosphoglucomutase‐3 deficiency; sIgE/sIgG, specific immunoglobulin E/specific immunoglobulin G; STAT3, signal transducer and activator of transcription 3
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Phosphoglucomutase 3 (PGM3) is an enzyme necessary for the synthesis of uridine diphosphate N-acetylglucosamine, an important precursor for protein glycosylation.1 Patients with PGM3 deficiency have ...a multisystemic disorder characterized by neurologic impairment and clinical features classically associated with autosomal-dominant hyper-IgE syndrome (AD-HIES) including recurrent pneumonias, skin abscesses, elevated levels of IgE, and abnormalities in connective tissues and bones.2-4 AD-HIES is caused by dominant negative mutations in the gene encoding signal transducer and activator of transcription 3 (STAT3), used for signaling by a wide range of cytokines and growth factors. The absence of the lower 100-kD band, corresponding to the unglycosylated gp130 isoform in the patients' lysates (Fig 2, B), is likely due to proteasomal degradation, as has been seen in another study.7 Our results are consistent with the observation that N-glycosylation inhibition of gp130 abolishes IL-6–driven STAT3 activation in cultured cardiac myocytes.8 Collectively, our findings demonstrate that defective glycosylation in PGM3-deficient patients results in reduced expression of unglycosylated gp130 protein and consequently, impaired gp130-dependent STAT3 phosphorylation. ...several reports showed that IL-27 plays a critical role in the suppression of TH2 responses.9 Altogether, these functional cellular phenotypes observed in PGM3-deficient patients overlap with STAT3 loss of function and gp130-deficient patients and mechanistically tie the PGM3 deficiency to poor gp130-dependent STAT3 signaling.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Immunologic investigations revealed normal numbers of total CD3+, CD4+, and CD8+ T cells and CD16+CD56+ natural killer cells but very low (0.1%) numbers of peripheral CD19+ B cells (see Table E1 in ...this article's Online Repository at www.jacionline.org). ...the diagnosis of agammaglobulinemia was established at that time, and the patient was treated with intravenous immunoglobulins. ...the functional replacement of the mouse E2A gene with a human HEB cDNA revealed that HEB, another E-protein member, can functionally compensate for the loss of E2A and rescue B-cell development.5 In contrast to previous E47-deficient patients,2 patient P2 had normal expression of IgM but decreased levels of CD27+ memory B cells, as well as switched memory CD27+IgD− B cells (Table I and see Fig E3 in this article's Online Repository at www.jacionline.org). ...she had an impaired antibody response to tetanus vaccine. Interestingly, it has been shown in mice that loss of E protein expression affects the CD8+ T-cell immune response.6 Indeed, genes associated with CD8+ effector activation and differentiation were upregulated, suggesting that E protein-deficient cells acquire a more effector T-cell transcriptional profile during the early stages of the immune response. ...in the absence of E2A protein, effector CD8+ T cells will exhibit a terminally differentiated shorter-lived effector phenotype.6 Furthermore, the index patient P1 had ALL. CD19 (%) IgG (g/L) IgA (g/L) IgM (g/L) TCF3 genotype Patient P1 0.1% Absent (0.96-2.04) Absent (0.37-1.8) Absent (0.43-2.83) Q270X/Q270X Patient P2 3% 6.75 (6.67-14.64) 0.67 (0.77-2.19) 0.18 (0.49-2.61) Q270X/Q270X Father 1.9% 8.91 (6.58-18.37) 3.21 (0.71-3.60) 0.21 (0.40-2.63) WT/Q270X Mother 2.0% 10.23 (6.58-18.37) 1.13 (0.71-3.60) 0.59 (0.40-2.63) WT/Q270X Healthy sister 5.3% 9.45 (6.58-18.37) 1.51 (0.71-3.60) 1.00 (0.40-2.63) WT/WT Healthy brother 2.4% 9.25 (6.13-15.12) 1.51 (0.57-2.56) 0.37 (0.70-2.84) WT/Q270X 1 A. Berglöf, J.J. Turunen, O. Gissberg, B. Bestas, K.E. Blomberg, C.I. Smith, Agammaglobulinemia: causative mutations and their implications for novel therapies, Expert Rev Clin Immunol, Vol. 12, 2013, 1205-1221 2 B. Boisson, Y.D. Wang, A. Bosompem, C.S. Ma, A. Lim, T. Kochetkov, A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCR(-) B cells, J Clin Invest, Vol. 123, 2013, 4781-4785 3 C. Murre, Helix-loop-helix proteins and lymphocyte development, Nat Immunol, Vol. 6, 2005, 1079-1086 4 G. Bain, E.C. Maandag, D.J. Izon, D. Amsen, A.M. Kruisbeek, B.C. Weintraub, E2A proteins are required for proper B cell development and initiation of immunoglobulin gene rearrangements, Cell, Vol. 79, 1994, 885-892 5 Y. Zhuang, R.J. Barndt, L. Pan, R. Kelley, M. Dai, Functional replacement of the mouse E2A gene with a human HEB cDNA, Mol Cell Biol, Vol. 18, 1998, 3340-3349 6 K.C. Lind, B.B. Wu, J.K. Fujimoto, A.W. Goldrath, Eur J Immunol, Vol. 42, 2012, 2031-2041 7 R. Somasundaram, M.A. Prasad, J. Ungerbäck, M. Sigvardsson, Transcription factor networks in B-cell differentiation link development to acute lymphoid leukemia, Blood, Vol. 126, 2015, 144-152 8 E. Tijchon, J. Havinga, F.N. van Leeuwen, B. Scheijen, B-lineage transcription factors and cooperating gene lesions required for leukemia development, Leukemia, Vol. 27, 2013, 541-552 9 C. Cobaleda, W. Jochum, M. Busslinger, Conversion of mature B cells into T cells by dedifferentiation to uncommitted progenitors, Nature, Vol. 449, 2007, 473-477
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The 10th Federation of African Immunological Societies (FAIS) Congress, held in Tunisia in November 2017, marked a significant scientific milestone. It enabled scientists from across the continent to ...promote immunology research and to showcase major achievements made by immunologists throughout Africa. This issue of the Journal of Leukocyte Biology (JLB) features manuscripts from the FAIS Congress. As noted in these papers, research in infectious diseases remains the focus of the African immunology community; however, increasingly noncommunicable diseases—such as autoimmunity, allergy, primary immunodeficiency, cancer and transplantation immunology—are also an emerging priority. This overview gives a brief history of the FAIS meeting, which also commemorated the 25th anniversary of the FAIS. It describes the current activities of the organization, as well as its history and the future opportunities for this Federation.
In 25 years the African immunology fraternity has expanded to 15 countries and is producing quality research in regionally relevant topics.
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Alveolar Macrophages play a key role in the development of a robust adaptive immune response against the agent of Tuberculosis (TB),
(
). However, macrophage response is often hampered by the ...production of IL-10, a potent suppressor of the host immune response. The secretion of IL-10 correlates with TB pathogenesis and persistence in host tissues. Concordantly, inhibition of IL-10 signaling, during BCG vaccination, confers higher protection against
through a sustained Th1 and Th17 responses. Therefore, uncovering host effectors, underlying mycobacteria-induced expression of IL-10, may be beneficial toward the development of IL-10-blocking tools to be used either as adjuvants in preventive vaccination or as adjunct during standard treatment of TB. Here, we investigated the role of FOXO3 transcription factor in mycobacteria-induced secretion of IL-10. We observed that PI3K/Akt/FOXO3 axis regulates IL-10 expression in human macrophages. Knocking down of FOXO3 expression resulted in an increase of IL-10 production in BCG-infected macrophages. The gene reporter assay further confirmed the transcriptional regulation of IL-10 by FOXO3.
analysis identified four Forkhead binding motifs on the human IL-10 promoter, from which the typical FOXO3 one at position -203 was the major target as assessed by mutagenesis and CHIP binding assays. Further, we also observed a decrease in gene expression levels of the M1 typical markers (i.e., CD80 and CD86) in SiFOXO3-transfected macrophages while activation of FOXO3 led to the increase in the expression of CD86, MHCI, and MHCII. Finally, co-culture of human lymphocytes with siFOXO3-transfected macrophages, loaded with mycobacterial antigens, showed decreased expression of Th1/Th17 specific markers and a simultaneous increase in expression of IL-4 and IL-10. Taken together, we report for the first time that FOXO3 modulates IL-10 secretion in mycobacteria-infected macrophage, driving their polarization and the subsequent adaptive immune response. This work proposes FOXO3 as a potential target for the development of host-directed strategies for better treatment or prevention of TB.
Autoimmune lymphoproliferative syndrome (ALPS) is a primary immunodeficiency disease due to impaired Fas‐Fas ligand apoptotic pathway. It is characterized by chronic nonmalignant, noninfectious ...lymphadenopathy and/or splenomegaly associated with autoimmune manifestations primarily directed against blood cells. Herein, we review the heterogeneous ALPS molecular bases and discuss recent findings revealed by the study of consanguineous patients. Indeed, this peculiar genetic background favored the identification of a novel form of AR ALPS‐FAS associated with normal or residual protein expression, expanding the spectrum of ALPS types. In addition, rare mutational mechanisms underlying the splicing defects of FAS exon 6 have been identified in AR ALPS‐FAS with lack of protein expression. These findings will help decipher critical regions required for the tight regulation of FAS exon 6 splicing. We also discuss the genotype‐phenotype correlation and disease severity in AR ALPS‐FAS. Altogether, the study of ALPS molecular bases in endogamous populations helps to better classify the disease subgroups and to unravel the Fas pathway functioning.
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