Human Adaptive Immunity Rescues an Inborn Error of Innate Immunity

Israël, Laura; Wang, Ying; Bulek, Katarzyna; Mina, Erika Della; Zhang, Zhao; Pedergnana, Vincent; Chrabieh, Maya; Lemmens, Nicole A.; Sancho‐Shimizu, Vanessa; Descatoire, Marc; Lasseau, Théo; Israelsson, Elisabeth; Lorenzo, Lazaro; Liu, Yi; Belkadi, Aziz; Moran, Andrew E.; Weisman, Leonard E.; Vandenesch, François; Batteux, Frédéric; Weller, Sandra; Levin, Michael; Herberg, Jethro; Abhyankar, Avinash; Prando, Carolina; Itan, Yuval; Wamel, Willem J. B. van; Pïcard, Capucine; Abel, Laurent; Chaussabel, Damien; Li, Xiaoxia; Beutler, Bruce; Arkwright, Peter D.; Casanova, Jean‐Laurent; Puel, Anne

doi:10.1016/j.cell.2017.01.039

Cited by 71 publications

(52 citation statements)

References 54 publications

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“…Blood donors of the Red Cross are normal healthy individuals that have been screened for infectious diseases, and this normal population is different from other control patients we have collected for other studies. Our results showed that under the normal conditions in the general population the anti-Hsp65 antibody is uncommon (2.8%) and this low prevalence in the normal population is consistent with the classic concept of human immunity that mycobacterial clearance is through the innate immunity, and the adaptive immunity (B-or T-cell activation) is only required to compensate for the deficiency of the innate immunity in the clearance of mycobacterial invasion [22]. Our data also showed that there are significantly elevated anti-Hsp65 antibodies in the patients with chronic diseases, such as Crohn's disease (CD) and Sjogren's syndrome (Sjo) [18,23].…”

Section: Discussionsupporting

confidence: 88%

“…It seems again that the human body responds to the invading mycobacteria in specific manners, but this specificity of the immune response does not appear conferred through the invading mycobacteria but the host genetic background, i.e., genetic susceptibility determines the host response to the environmental microbes. It should be noted that viral immunity and viral vaccination is entirely different from bacterial/mycobacterial immunity in which non-specific innate immunity plays a major role, whereas in viral immunity a specific adaptive immunity with memory is shown to be the major protective mechanism [22,29].…”

Section: Discussionmentioning

confidence: 99%

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Serological Testing for Mycobacterial Heat Shock Protein Hsp65 Antibody in Health and Diseases

Zhang¹,

Minardi²,

Kuenstner³

et al. 2019

Microorganisms

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Mycobacterial heat shock protein 65 gene (Hsp65) has been widely used for classification of Mycobacterial species, and detection of Mycobacterial genes by molecular methods and has proven useful in identification of Mycobacterial infection in various clinical conditions. Circulating antibody against Mycobacterial hsp65 has been found in many clinical diseases including autoimmune diseases (Crohn’s disease, lupus erythematosus, multiple sclerosis, diabetes, etc.), atherosclerosis and cancers. The prevalence of anti-Hsp65 antibody in the normal healthy population is unknown. We determined the blood levels of antibody against Mycobacterial hsp65 in the normal population represented by 288 blood donors of the American Red Cross and tested the blood of 109 patients with Crohn’s disease and 28 patients with Sjogren’s syndrome for comparison. The seroprevalence of anti-Hsp65 IgG in the normal population of Red Cross donors was 2.8% (8 of 288 positive). The Hsp65 antibody levels were significantly elevated in patients with Crohn’s disease and Sjogren’s syndrome. The prevalence of Hsp65 antibody in Crohn’s disease patients was 67.9% (74 of 109 patients), and 85.7% for Sjogren’s patients (24 of 28 patients). Our data indicate that anti-Hsp65 antibody is rare in the normal population, but frequent in chronic diseases. The presence of circulating Hsp65 antibody reflects an abnormal immune (adaptive) response to Mycobacterial exposure in patients with chronic diseases, thus differentiating the patients with chronic diseases from those clinical mimics.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Serological Testing for Mycobacterial Heat Shock Protein Hsp65 Antibody in Health and Diseases

Zhang¹,

Minardi²,

Kuenstner³

et al. 2019

Microorganisms

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show abstract

“…Blood donors of the Red Cross are normal healthy individuals that have been screened for infectious diseases, and this normal population is different from other control patients we have collected for other studies. Our results showed that under the normal conditions in the general population the anti-microbial antibodies are uncommon (2 -5.6% as shown in Table 1), and this low prevalence of anti-microbial antibodies in the normal population is consistent with the classic concept of human immunity that the bacterial clearance is through the innate immunity, and the adaptive immunity (B-or T-cell activation) is only required to compensate the deficiency of the innate immunity in the clearance of bacterial invasion [20] . There is also a large quantity of immunoglobulins in circulation, such as IgG, IgA or IgM that can bind to the specific bacterial proteins such as the protein A of S. aureus, or the protein G of Streptococcus with high affinity so that the invading bacteria will be cleared rapidly by the complement/phagocytes from the circulation [21][22][23] .…”

Section: Anti-microbial Antibodies Have Been Used For Diagnosis Of MIsupporting

confidence: 79%

Seroprevalence of anti-microbial antibodies in the normal healthy population with implications in chronic diseases

Zhang¹,

Minardi²,

Kuenstner³

et al. 2019

Preprint

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We have previously discovered a panel of anti-microbial antibodies from patients with Crohn's disease (CD) and Sjogren's syndrome (Sjo). We have also demonstrated the increase of these anti-microbial antibodies in other autoimmune disease such as rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis in a small number of cases. The seroprevalence of these antibodies in the normal healthy population is unknown. We set to survey the normal population for these anti-microbial antibodies. We collected 288 blood samples from the donor units of the leukocytereduced red blood cells from the American Red Cross, and examined the presence of the anti-microbial antibodies in these blood samples using direct ELISA assays established in our laboratory using the recombinant microbial protein antigens. Our results showed that the prevalence of RPOB antibody in the normal blood donor population is 2.4% (7 positive of 288 samples). The prevalence of EF-G antibody is 4.2% (12 positive of 288 samples), ATP5a 5.2% (15 positive), Hsp65 2.8% (8 positive), EF-Tu 5.6% (16 positive), and NMPC 4.2% (12 positive). Meanwhile, in 109 patients with Crohn's disease and 28 patients with Sjogren's syndrome, these anti-bacterial antibodies are significantly increased (p<0.001). These results indicate that the specific anti-microbial antibodies within the normal general population are uncommon, but frequent in chronic disease states. The presence of increased anti-microbial antibodies in the blood of patients but not in normal controls can serve as biomarkers for chronic diseases such as Crohn's disease and Sjogren's, and their presence indicates abnormal B-cell/plasma cell function in response to the commensal/pathogenic microbes. Since the antigens were derivedfrom the common microbes present on the surface of the normal population, the antimicrobial antibodies in patients with diseases but not in the normal population suggest a deficient clearance of the microbes from the circulation by the innate immunity system in chronic diseases. These results also raise questions of bacterial vaccination using whole bacterial extracts as these anti-bacterial antibodies appear pathogenic rather than protective, offering fresh thinking in designing bacterial vaccines as preventive or therapeutic measures in chronic diseases such as Crohn's disease and Sjogren's Disease.

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“…Other extra-hematopoietic manifestations, reflecting the breadth of NF-κB physiology are also present. With the recognition of infectious diseases as monogenic inborn errors of immunity, the description of mutations in other genes, upstream or downstream from IκBα, should gradually elucidate the pathogenesis of other infectious and immunological phenotypes affecting EDA-ID patients [69–71], as illustrated by the discovery of mutations in the BCL10-CARD core complex [72] or in the TIR pathway [51–53, 73–75]. These mutations provide explanations for some of the immunological and clinical phenotypes common to patients with hypomorphic IKBKG/NEMO mutations or hypermorphic NFKBIA/ IκBα mutations, such as excessively high numbers of naïve B and T cells.…”

Section: Discussionmentioning

confidence: 99%

Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency

et al. 2017

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Germline heterozygous gain-of-function (GOF) mutations of NFKBIA, encoding IκBα, cause an autosomal dominant (AD) form of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID). Fourteen unrelated patients have been reported since the identification of the first case in 2003. All mutations enhance the inhibitory activity of IκBα, by preventing its phosphorylation on serine 32 or 36 and its subsequent degradation. The mutations certainly or probably occurred de novo in 13 patients, whereas it was inherited from a parent with somatic mosaicism in one patient. Eleven mutations, belonging to two groups, have been identified: (i) missense mutations affecting S32, S36, or neighboring residues (8 mutations, 11 patients) and (ii) nonsense mutations upstream from S32 associated with the reinitiation of translation downstream from S36 (3 mutations, 3 patients). Thirteen patients had developmental features of EDA, the severity and nature of which differed between cases. All patient cells tested displayed impaired NF-κB-mediated responses to the stimulation of various surface receptors involved in cell-intrinsic (fibroblasts), innate (monocytes), and adaptive (B and T cells) immunity, including TLRs, IL-1Rs, TNFRs, TCR, and BCR. All patients have profound B-cell deficiency. Specific immunological features, found in some, but not all patients, include a lack of peripheral lymph nodes, lymphocytosis, dysfunctional α/β T cells, and a lack of circulating γ/δ T cells. The patients had various pyogenic, mycobacterial, fungal, and viral severe infections. Patients with a missense mutation tend to display more severe phenotypes, probably due to higher levels of GOF proteins. In the absence of hematopoietic stem cell transplantation (HSCT), this condition can cause death before the age of 1 year (one child). Two survivors are on prophylaxis (at 9 and 22 years). Six children died after HSCT. Five survived, four of whom are on prophylaxis (3 to 21 years post HSCT), whereas one is well with no prophylaxis. Heterozygous GOF mutations in IκBα underlie a severe and syndromic immunodeficiency, the inter-individual variability of which might partly be ascribed to the dichotomy of missense and nonsense mutations, and the hematopoietic component of which can be rescued by HSCT.

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Human Adaptive Immunity Rescues an Inborn Error of Innate Immunity

Abstract: Graphical abstract Adaptive immunity can compensate for a defect in the innate immune response, as seen with humans lacking a key TLR adaptor who can mount an antibody response to a bacterial pathogen.

Cited by 71 publications

References 54 publications

Serological Testing for Mycobacterial Heat Shock Protein Hsp65 Antibody in Health and Diseases

Serological Testing for Mycobacterial Heat Shock Protein Hsp65 Antibody in Health and Diseases

Seroprevalence of anti-microbial antibodies in the normal healthy population with implications in chronic diseases

Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency

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