Déficit immunitaire primitif par défaut d'expression des antigènes HLA de classe II: neuf observations tunisiennes

doi:10.1016/S0929-693X(99)80005-0

Archives de Pédiatrie

Volume 5, Issue 10, October 1998, Pages 1089-1093

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Résumé

Les déficits immunitaires primitifs par défaut d'expression des antigènes HLA de classe II sont des affections rares. La majorité des cas rapportés dans la littérature sont d'origine maghrébine. Neuf nouveaux cas tunisiens sont rapportés.

Population et méthodes

Sur une période de 5 ans, le diagnostic de déficit immunitaire primitif par défaut d'expression des antigènes HLA de classe Il a été établi chez neuf enfants appartenant à sept familles différentes. L'expression des antigènes HLA de classe II a été étudiée par immunomarquage avec lecture en cytométrie de flux.

Résultats

Les premières infections sont apparues en moyenne à l'âge de 4,9 mois (2–10 mois); elles sont dominées par une diarrhée d'emblée chronique (huit cas). Des infections récidivantes se sont ultérieurement associées: pneumopathies (sept cas), muguet buccal (sept cas), otites (cinq cas), septicémies (quatre cas), ainsi que des manifestations allergiques (quatre cas). Six patients sont décédés à un âge moyen de 30 mois, dans un état de dénutrition grave. L'expression des antigènes HLA de classe II est nulle dans tous les cas. Les lymphocytes TCD4+ sont diminués dans sept cas. Les proliférations lymphocytaires sont effondrées en présence des antigènes testés. Quatre patients ont une panhypogammaglobulinémie.

Conclusion

Cette étude confirme la fréquence des déficits immunitaires primitifs par défaut d'expression des antigènes HLA de classe II parmi la population maghrébine. La sévérité des infections, notamment digestives, doit faire évoquer le diagnostic. L'évolution est fatale en dehors de la greffe de moelle osseuse.

Summary

Background

Bare lymphocyte syndrome is a rare inherited primary immunodeficiency. The majority of the patients reported to date are from North Africa. We report nine new Tunisian cases.

Population and methods

Over a period of 5 years, we have established the diagnosis of bare lymphocyte syndrome in nine patients who belong to seven different families. Class II HLA antigen expression was studied on resting peripheral mononuclear cells and PHA blasts.

Results

The clinical symptoms started at the mean age of 4.5 months (2–10 months) with chronic diarrhea. The evolution was characterized by appearance of other recurrent infections: pneumopathies (seven cases), thrush (seven cases), otitis (five cases) and septicemia (four cases). Allergic manifestations were observed in four cases. Six patients died at the mean age of 30 months from severe dénutrition. Class II HLA antigens were not expressed on resting and activated lymphocytes. The absolute count of TCD4+ lymphocytes was decreased in seven patients. Lymphoproliferative response to specific antigens was absent. Four patients had panhypogammaglobulinemia.

Conclusion

This study confirms the frequency of this disease among the North African population. The severity of the recurrent infection suggests the diagnosis of bare lymphocyte syndrome. This disease is fatal in the absence of bone marrow transplantation.

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Cited by (15)

Major Histocompatibility Complex Class II Deficiency
2016, Encyclopedia of Immunobiology
Major histocompatibility complex (MHC) class II deficiency, also called the bare lymphocyte syndrome, is a rare primary immunodeficiency disease characterized by a virtual absence of MHC class II expression associated with a variable reduction in MHC class I expression. The disease is genetically heterogeneous. It can result from loss-of-function mutations in any one of four genes – CIITA, RFX5, RFXAP, and RFXANK – encoding regulatory factors required for transcription of class I and/or class II MHC genes. RFX5, RFXAP, and RFXANK encode subunits of regulatory factor X, a DNA-binding transcription factor required for transcription of both class I and class II MHC genes. Class II transactivator (CIITA) encodes a transcriptional coactivator showing high specificity for MHC class II genes. CIITA is referred to as the ‘master regulator’ of MHC class II genes because its highly regulated pattern of expression dictates most qualitative and quantitative aspects of MHC class II expression. At MHC class I promoters, CIITA is replaced by a related coactivator, NLRC5. Deficient MHC expression leads to the inability to mount antigen-specific adaptive immune responses against infectious agents. Patients consequently suffer from a broad range of severe and recurrent infections, generally resulting in death at a young age, unless they are treated by hematopoietic stem cell transplantation.
Major histocompatibility complex class II expression deficiency caused by a RFXANK founder mutation: A survey of 35 patients
2011, Blood
Citation Excerpt :
Hypogammaglobulinemia and low CD4 T-cell counts are found in most patients.2 Impaired T- and B-cell immunity results in susceptibility to a broad range of viral, bacterial, fungal, and protozoan infections.3-5 Infections generally occur in the first year of life and involve the respiratory and gastrointestinal tracts.2,4,5
Inherited deficiency of major histocompatibility complex (MHC) class II molecules impairs antigen presentation to CD4⁺ T cells and results in combined immunodeficiency (CID). Autosomal-recessive mutations in the RFXANK gene account for two-thirds of all cases of MHC class II deficiency. We describe here the genetic, clinical, and immunologic features of 35 patients from 30 unrelated kindreds from North Africa sharing the same RFXANK founder mutation, a 26-bp deletion called I5E6-25_I5E6 + 1), and date the founder event responsible for this mutation in this population to approximately 2250 years ago (95% confidence interval [CI]: 1750-3025 years). Ten of the 23 patients who underwent hematopoietic stem cell transplantation (HSCT) were cured, with the recovery of almost normal immune functions. Five of the patients from this cohort who did not undergo HSCT had a poor prognosis and eventually died (at ages of 1-17 years). However, 7 patients who did not undergo HSCT (at ages of 6-32 years) are still alive on Ig treatment and antibiotic prophylaxis. RFXANK deficiency is a severe, often fatal CID for which HSCT is the only curative treatment. However, some patients may survive for relatively long periods if multiple prophylactic measures are implemented.
Hematopoietic stem cell transplantation and other management strategies for MHC class II deficiency
2010, Immunology and Allergy Clinics of North America
Citation Excerpt :
Most patients are of North African origin (Algeria, Tunisia, and Morocco)2,12,13 (Picard, unpublished data, 2010). Other patients have diverse ethnic backgrounds, including Israel, the Kingdom of Saudi Arabia, Pakistan, Turkey, France, Holland, Italy, Spain, and the United States of America.2,12,14–16 Half of the reported cases have RFXANK deficiency (they belong to the complementation group B),2 75% of which are of North African descent (Morocco, Algeria, and Tunisia).
Major histocompatibility complex class II deficiency
2007, Anales de Pediatria
El déficit de expresión de moléculas de clase II del complejo mayor de histocompatibilidad es una inmunodeficiencia primaria combinada de herencia autosómica recesiva. Presenta mayor prevalencia en los países mediterráneos, sobre todo en el norte de África. La precocidad en el diagnóstico es vital, dada su elevada letalidad en los primeros 2 años de vida, así como su potencial tratamiento mediante trasplante de progenitores hematopoyéticos. Se presenta una revisión de 4 casos mediante la descripción de las características epidemiológicas y clínicas, las pruebas diagnósticas, el abordaje terapéutico y la posterior evolución.
Major histocompatibility complex class II deficiency is an autosomal recessive primary combined immunodeficiency. The prevalence of this deficiency is highest in Mediterranean areas, especially north Africa. Early diagnosis is essential due to high mortality in the first 2 years of life and the possibility of bone marrow transplantation. We report four cases of major histocompatibility complex class II deficiency and describe their epidemiologic and clinical characteristics, diagnostic tests, treatment and outcome.
Prevalence of Pneumocystis Jiroveci pneumonia in Tunisian primary immunodeficient patients
2007, Archives de Pediatrie
La pneumopathie à Pneumocystis Jiroveci (PPJ) est une infection opportuniste peu fréquente dans notre pays, ainsi que dans d'autres pays africains incluant ceux avec une prévalence élevée du sida. Dans la littérature, la PPJ a également été rapportée au cours des déficits immunitaires héréditaires (DIH) notamment les SCID T^–B^– ou T^–B⁺ et le syndrome d'hyper-IgM dans sa forme liée à l'X.
Évaluer la prévalence de la PPJ au cours des différents types de DIH observés en Tunisie.
Une étude rétrospective a concerné 290 cas de DIH confirmés par l'exploration de l'immunité cellulaire et humorale, spécifique et non spécifique. La recherche de P. Jiroveci sur liquide de lavage bronchoalvéolaire a été effectuée chez les malades suspects de pneumocystose.
Une association entre DIH et une infection à P. Jiroveci, confirmée parasitologiquement, a été retrouvée chez 9 sur 290 patients (3 %) parmi lesquels une majorité (7) était atteinte d'un déficit immunitaire combiné par défaut d'expression des molécules HLA de classe II (DIC HLA II-). Il s'agit d'une affection autosomique récessive particulièrement fréquente dans la population maghrébine qui est caractérisée par un taux élevé de consanguinité. Aucune PPJ associée à un SCID T^–B^– ou T^–B⁺ ou à un syndrome d'hyper-IgM lié à l'X n'a été observée.
La PPJ est donc particulièrement fréquente au cours du DIC HLA II- puisqu'elle est retrouvée dans 7 sur 22 cas diagnostiqués avec ce déficit (31 %). Par ailleurs, ces résultats observés chez des enfants dont les cellules présentatrices sont incapables de présenter l'antigène aux lymphocytes T par défaut d'expression des molécules HLA de classe II confirment le rôle critique des réponses T CD4⁺ dans la réponse immune contre ce pathogène.
Pneumocystis Jiroveci pneumonia (PJP) is a rare opportunistic infection in immunodeficient patients in Tunisia, as well as in other Africain countries including those with a high prevalence of AIDS. In the literature, PJP has been reported in primary immunodeficiency diseases (PID) namely SCID T^–B^– or T^–B⁺ or X-linked hyper-IgM syndrome.
To evaluate the prevalence of PJP in the different PID observed in Tunisia.
This retrospective study concerned 290 cases of PID confirmed by immunological investigation including the study of specific and/or non-pecific humoral and cellular immunity. The identification of P. Jiroveci in patients suspected of pneumocystosis was achieved by parasitological investigation in bronchoalveolar lavages.
A PID associated to a parasitologically confirmed pneumocystic infection was found in 9 out of 290 patients (3%) among whom the majority (7 patients) had an HLA class II combined immunodeficiency. The latter is an autosomic recessive disease which has been reported mainly in North African families. Indeed, this population is characterized by a high rate of consanguinity. Interestingly, no PJP has been observed neither in SCID T^–B^– or T^–B⁺ nor in X-linked hyper-IgM syndrome.
PJP seems to be particularly frequent in HLA class II deficiency patients, since 7 out of 22 patients with this deficiency had a PJP (31%). Due to this defect, antigen presenting cells are unable to present the antigen to T lymphocytes demonstrating the critical role of CD4⁺ T lymphocytes responses in the immune response to this pathogen.
A case of bronchiolitis due to pneumocystis lung infection related to major histocompatibility class II deficiency
2006, Revue des Maladies Respiratoires
Malgré son apparence banale, la bronchiolite peut être l’évènement révélateur de nombreuses pathologies, notamment malformatives ou dysimmunitaires. Nous rapportons un diagnostic différentiel rare et grave de la bronchiolite du nourrisson: le défaut d’expression des molécules du complexe majeur d’histocompatibilité (CMH) de classe II, déficit immunitaire à transmission autosomique récessive.
Un nourrisson de 8 mois a été hospitalisé pour une bronchiolite hypoxémiante. Un déficit immunitaire a été suspecté devant l’aspect traînant de la symptomatologie et l’association d’une courbe pondérale médiocre. Le lavage broncho-alvéolaire a permis le diagnostic de pneumocystose et les explorations immunitaires ont conclu à un défaut d’expression des molécules HLA de classe II.
Le déficit en HLA de classe II affecte les réponses immunitaires humorales et cellulaires. Il est à l’origine d’infections sévères essentiellement broncho-pulmonaires et digestives avec diarrhée chronique. Ces manifestations apparaissent en général au cours des premiers mois de vie. Le pronostic est sombre en l’absence de greffe de moelle osseuse.
Despite occurring commonly in children bronchiolitis can also be the presenting feature of other disorders particularly congenital malformations and immunological diseases. We report a rare and severe cause of bronchiolitis: major histocompatibility (MHC) class II deficiency, an autosomal recessive disease.
An eight month old infant was admitted with hypoxic bronchiolitis. An immunodeficiency disease was suspected based on lingering symptoms associated with poor weight gain. Microbiologic tests revealed an infection with Pneumocystis carinii and immunologic investigations allowed us to make the diagnosis of MHC class II deficiency.
The lack of MHC class II expression results in a severe defect in both humoral and cellular immune responses to foreign antigens. It is characterised by recurrent bronchopulmonary infections and chronic diarrhoea. The clinical onset occurs within the first months of life. Prognosis is very poor when bone marrow transplantation cannot be performed.

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Déficit immunitaire primitif par défaut d'expression des antigènes HLA de classe II: neuf observations tunisiennesMajor histocompatibility class II antigen deficiency: nine new Tunisian cases

Résumé

Population et méthodes

Résultats

Conclusion

Summary

Background

Population and methods

Results

Conclusion

J Pediatr

J Pediatr

Blood

Immunol Today

Blood

J Pediatr

Blood