Jean-Laurent Casanova

Génétique humaine de la tuberculose

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a major public health problem worldwide, resulting in 8.7 million new cases and 1.4 million deaths each year. One third of the worlds population is exposed to M. tuberculosis and, after exposure, most, but not all, individuals become infected. Among infected subjects, only a minority (∼10%) will eventually develop clinical disease, which is typically either a primary, often extra-pulmonary, TB in children, or a reactivation, pulmonary TB in adults. Considerable genetic epidemiological evidence has accumulated to support a major role for human genetic factors in the development of TB. Numerous association studies with various candidate genes have been conducted in pulmonary TB, with very few consistent results. Recent genome-wide association studies revealed only a modest role for two inter-genic polymorphisms. However, a first major locus for pulmonary TB was mapped to chromosome 8q12-q13 in a Moroccan population after a genome-wide linkage screen. Using a similar strategy, two other major loci controlling TB infection were recently identified. While the precise identification of these major genes is ongoing, the other fascinating observation of these last years was the demonstration that TB can also reflect a Mendelian predisposition. Following the findings obtained in the syndrome of Mendelian susceptibility to mycobacterial diseases, several children with complete IL-12Rβ1 deficiency, were found to have severe TB as their sole phenotype. Overall, these recent findings provide the proof of concept that the human genetics of TB involves a continuous spectrum from Mendelian to complex predisposition with intermediate major gene involvement. The understanding of the molecular genetic basis of TB will have fundamental immunological and medical implications, in particular for the development of new vaccines and treatments.

Recurrent Salmonellosis in a Child with Complete IL-12Rβ1 Deficiency.

A 3 year old boy presented with fever, abdominal pain and cervical lymphadenopathy. He had previously been treated empirically with anti-tuberculous therapy twice, at age 9 months and 27 months, for peripheral lymphadenopathy. An older sibling died of suspected tuberculous meningitis. Mantoux test was normal. Bone marrow and lymph node biopsy ruled out lymphoma and absolute neutrophil and lymphocyte counts were normal. Blood and lymph node cultures were positive for Salmonella typhi. The childs symptoms resolved with IV ceftriaxone and he was discharged. Over the next 2 years, the child was admitted every 2-3 months for culture positive S. typhi bacteremia with complaints of fever, abdominal distention and dysentery. HIV workup was negative. A prolonged course of probenicid and high dose amoxicillin increased interval between episodes to 4-5 months only. Cholecystectomy was debated and deferred due to suspicion of immunodeficiency. Blood samples from patient and parents were sent to France for workup and IL-12Rβ1 deficiency was found. Parental counseling and subsequent patient management remained difficult in view of financial constraints and outstation residence of family. At age 7 years, the child presented with small bowel obstruction. He was managed conservatively with antibiotics, IV fluids and blood transfusions, but eventually succumbed to endotoxic shock. This case highlights the importance of considering IL-12Rβ1 deficiency in children with repeated salmonellosis, a diagnosis which precludes intensive and aggressive monitoring and management of the patient in scenarios where bone marrow transplants are not feasible.

Human Interleukin-12—Interferon-γ Axis in Protective Immunity to Mycobacteria

The genus Mycobacterium comprises more than 85 species of Gram-positive acid-fast aerobic bacilli. M. tuberculosis is the agent of tuberculosis, which preferentially affects lungs and lymph nodes; M. leprae is responsible for leprosy, a disease of peripheral nerves and skin; and M. ulcerans is the agent of cutaneous Buruli ulcer. These three species are the most pathogenic of the known mycobacteria, but not all infected individuals develop clinical disease. The remaining mycobacterial species are environmental and poorly pathogenic in humans. However, environmental mycobacteria (EM) and Bacille Calmette-Guerin (BCG) vaccine substrains may be responsible for severe infections in patients with impaired immunity. Thus, even following infection with a virulent species, the appearance of clinical mycobacterial disease implies that host defenses have failed.

Immunodeficiencies at the Interface of Innate and Adaptive Immunity

Abstract In the last 20 years, new primary immunodeficiencies (PIDs) affecting the immunity mediated by interferon (IFN)-γ, IFN-α/β-λ, Toll and interleukin-1 receptor (TIR) domain nuclear factor (NF)-κB, Toll-like receptor (TLR)-3 pathway, and interleukin (IL)-17 have been identified. Some of these genetic defects are “conventional” PIDs, associated with a broad range of infections, but others provide a molecular explanation for severe pediatric infectious diseases previously thought to be idiopathic. These “nonconventional” PIDs may be associated with severe and/or recurrent infections caused by a single family of microorganisms, a situation strongly contrasting with that for “conventional” PIDs. Standard immunological explorations are generally normal in these patients, whether they are susceptible to one infection or to many infectious agents. Despite the lack of a clear immunological abnormality, infections in these patients are typically severe and often fatal. All these disorders were initially thought to be rare, but they have since been diagnosed in about 800 patients around the world.

Human Genetics of Tuberculosis of the Nervous System

Central nervous system (CNS) disease caused by Mycobacterium tuberculosis is a devastating manifestation of tuberculosis (TB) in children. CNS TB accounts for 10% of all cases of extrapulmonary TB, with high neurological morbidity and mortality rates. The diagnosis of CNS TB remains challenging, in particular in children, as clinical features are nonspecific, bacteriological confirmation is commonly missing, and laboratory tests are insensitive. The resulting treatment delay is often the strongest risk factor for poor outcomes. While the pathogenesis of CNS TB remains poorly understood, recent findings showed that some cases of severe childhood TB could be explained by single-gene inborn errors of immunity involving the IL-12/IL-23-IFN-γ pathway. In the present study, we describe the first cases of such genetic defects in two Moroccan patients with clearly documented CNS TB. The first patient presented an autosomal recessive TYK2 deficiency leading to an impaired response to IL-12 and a resulting impaired IFN-γ production. The second patient had an autosomal dominant STAT1 deficiency affecting the response to IFN-γ. These observations also provide further support to the hypothesis that severe TB of childhood is not only an infectious disease but also a genetic disorder at least in some instances. They also pave the way for the development of new treatments based on pathophysiology such as the administration of recombinant IFN-γ in patients who have an impaired production of this cytokine.

Variant of X-Linked Chronic Granulomatous Disease Revealed by a Severe Burkholderia cepacia Invasive Infection in an Infant

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by increased susceptibility to bacteria and fungi since early in life, caused by mutations in any of the five genes coding for protein subunits in NADPH oxidase. X-linked variant CGD can be missed during routine evaluation or present later in life due to hypomorphic mutations and a residual superoxide production. The case of a 10-month-old boy who died of pneumonia is reported. The isolation of Burkholderia cepacia from his lung, together with a marginally low nitroblue tetrazolium reduction assay (NBT), made us suspect and pursue the molecular diagnosis of CGD. A postmortem genetic analysis finally demonstrated CGD caused by a hypomorphic missense mutation with normal gp91phox expression. In a patient being investigated for unusually severe or recurrent infection, a high index of suspicion of immunodeficiency must be maintained.

ArticlesClinical features of dominant and recessive interferon γ receptor 1 deficiencies

BACKGROUND Interferon gamma receptor 1 (IFNgammaR1) deficiency is a primary immunodeficiency with allelic dominant and recessive mutations characterised clinically by severe infections with mycobacteria. We aimed to compare the clinical features of recessive and dominant IFNgammaR1 deficiencies. METHODS We obtained data from a large cohort of patients worldwide. We assessed these people by medical histories, records, and genetic and immunological studies. Data were abstracted onto a standard form. FINDINGS We identified 22 patients with recessive complete IFNgammaR1 deficiency and 38 with dominant partial deficiency. BCG and environmental mycobacteria were the most frequent pathogens. In recessive patients, 17 (77%) had environmental mycobacterial disease and all nine BCG-vaccinated patients had BCG disease. In dominant patients, 30 (79%) had environmental mycobacterial disease and 11 (73%) of 15 BCG-vaccinated patients had BCG disease. Compared with dominant patients, those with recessive deficiency were younger at onset of first environmental mycobacterial disease (mean 3.1 years [SD 2.5] vs 13.4 years [14.3], p=0.001), had more mycobacterial disease episodes (19 vs 8 per 100 person-years of observation, p=0.0001), had more severe mycobacterial disease (mean number of organs infected by Mycobacterium avium complex 4.1 [SD 0.8] vs 2.0 [1.1], p=0.004), had shorter mean disease-free intervals (1.6 years [SD 1.4] vs 7.2 years [7.6], p<0.0001), and lower Kaplan-Meier survival probability (p<0.0001). M avium complex osteomyelitis was more frequent in dominant than in recessive patients (22/28 [79%] vs 1/8 [13%], p=0.002), and this disorder without other organ involvement arose only in dominant patients (9/28 [32%]). Disease caused by rapidly growing mycobacteria was present in more recessive than dominant patients (7/22 [32%] vs 1/38 [3%], p=0.002). INTERPRETATION Recessive complete and dominant partial IFNgammaR1 deficiencies have related clinical phenotypes, but are distinguishable by age at onset, dissemination, and clinical course of mycobacterial diseases. A strong correlation exists between IFNGR1 genotype, cellular responsiveness to interferon gamma, and clinical disease features.