Molecular epidemiology of poliovirus infection in Tunisia.

This report is an overview of poliomyelitis surveillance in Tunisia from 1991 to 1996. In all, 2088 stool specimens, collected from 152 acute flaccid paralysis (AFP) cases and from 1747 of their healthy contacts were investigated. Virus isolation was done systematically in RD and HEp-2C cell lines and isolated viruses were typed by sero-neutralisation as polioviruses or non-polio enteroviruses. Poliovirus isolates were analysed systematically for their wild or vaccine-related origin by two methods--one based on antigenic differences and one on genetic differences between strains. All type 2 polioviruses were vaccine-related and most wild viruses belonged to polio serotype 3. Wild polio type 3 viruses were detected in 1991 and 1992 in six cases of paralytic polio. A silent circulation of wild polio 1 and wild polio 3 was detected in 1994. No wild virus was detected in Tunisia from 1995 onwards. Wild polioviruses were sequenced and compared with Tunisian wild strains isolated during the 1980s, as well as other genotypes from the international database. These investigations revealed a single Tunisian polio 3 genotype that has been circulating from 1985 to 1994 and two different polio 1 genotypes. These results reflect effective control strategies within the country and contribute to the improvement of the polio eradication programme effectiveness at national and global levels.     

RAG-dependent primary immunodeficiencies

Mutations in recombination activating genes 1 and 2 (RAG1 and RAG2) cause a spectrum of severe immunodeficiencies ranging from classical T cell-B cell-severe combined immunodeficiency (T(-)B(-)SCID) and Omenn syndrome (OS) to an increasing number of peculiar cases. While it is well established from biochemical data that the specific genetic defect in either of the RAG genes is the first determinant of the clinical presentation, there is also increasing evidence that environmental factors play an important role and can lead to a different phenotypic expression of a given genotype. However, a better understanding of the mechanisms by which the molecular defect impinges on the cellular phenotype of OS is still lacking. Ongoing studies in knock-in mice could better clarify this aspect.     

Rubella infection in children and teenagers in Tunisia

Rubella is a worlwide common infection; its importance in public health relates to the risk of malformation when primary infection occurs during pregnancy. This serosurvey was conducted to assess the kinetics of rubella infection in Tunisian children and teenagers and to determine the proportion of girls who remain seronegative at childbearing age. The studied population included 2481 individuals aged seven (N =1136), 13 (N =711) and 19 years (N =634), this sample was collected in 1996 and is representative of all geographical regions of the country. Our results indicate that 42% of tunisians are infected before seven years, 73% before 13 and 89% before 19 years of age. These rates are lower than those previously reported in the country. The proportion of seronegatives at 19 years of age was higher in costal regions than in the rest of the country: 14 vs 5% (p =0,0008). This difference should be due to the higher socio-economic level of the population living in costal regions. Our study indicates that primary infection with rubella virus in Tunisia is progressively shifting to older ages, which may increase the risk of congenital rubella syndrome. The introduction of rubella vaccination in the national program of vaccination may be considered, however only very high coverage levels will have a positive effect. Beside the reduction of the risk of congenital rubella syndrome, rubella vaccination will reduce the incidence of febrile rush cases and thus facilitate the surveillance activities conducted as part of the national program of measles elimination.     

Autoimmunity in primary T-cell immunodeficiencies

Primary immunodeficiency diseases (PID) are a genetically heterogeneous group of more than 270 disorders that affect distinct components of both humoral and cellular arms of the immune system. Primary T cell immunodeficiencies affect subjects at the early age of life. In most cases, T-cell PIDs become apparent as combined T- and B-cell deficiencies. Patients with T-cell PID are prone to life-threatening infections. On the other hand, non-infectious complications such as lymphoproliferative diseases, cancers and autoimmunity seem to be associated with the primary T-cell immunodeficiencies. Autoimmune disorders of all kinds (organ specific or systemic ones) could be subjected to this class of PIDs; however, the most frequent autoimmune disorders are immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA). In this review, we discuss the proposed mechanisms of autoimmunity and review the literature reported on autoimmune disorder in each type of primary T-cell immunodeficiencies.     

Mycobacterial diseases in primary immunodeficiencies

Primary immunodeficiency diseases comprise over 100 conditions, each associated with a variety of viral, bacterial, fungal and protozoan infections. M. tuberculosis and less virulent mycobacteria, such as bacille Calmette-Guérin vaccines and environmental non-tuberculous mycobacteria, may cause severe disease in patients with primary immunodeficiency diseases. However, no previous review has dealt with the issue of which primary immunodeficiency diseases predispose affected individuals to mycobacterial disease. This information is very useful, not only increasing our understanding of human immunity to mycobacteria, but also for the diagnostic investigation of patients with mycobacteriosis. We review here the medical literature on cases of mycobacterial disease in patients with primary immunodeficiency diseases.     

Leukocyte interferon reaction in patients with primary immunodeficiencies

The capacity of leukocytes from children with primary immunodeficiency to produce alpha- and gamma-interferons in vitro was studied. Interferon response of leukocytes in most of the patients examined was found to be practically unchanged. The immunostimulating therapy in some cases exerted a regulating effect on leukocyte capacity for interferon production. It is assumed that the interferon-producing function of T lymphocytes may be preserved in patients suffering from primary immunodeficiency.     

Interferon production in primary immunodeficiencies

Alpha- and gamma-interferon (IFN) production by peripheral blood mononuclear cells (PBMC) from 18 patients affected by primary immunodeficiency syndromes was examined and compared with that of 20 normal donors. Patients included 8 with common variable immunodeficiency (CVI), 2 with congenital agammaglobulinemia, 4 with ataxia-telangiectasia, 2 with hyper-IgE syndrome, 1 with chronic EBV infection, 1 with combined immunodeficiency, and 1 with immunodeficiency with hyper-IgM. No spontaneous IFN production was observed in either patients and controls. Newcastle disease virus-induced alpha-IFN production was found to be normal in all patients. Gamma-IFN was induced by both galactose oxidase and staphylococcal enterotoxin (B). Gamma-interferon production was low or undetectable in patients with ataxia-telangiectasia, in immunodeficiency with hyper-IgM, and in hyper-IgE syndrome. No major defect of gamma-IFN was found in other types of immunodeficiency, despite the presence of occasional low producers (1 of 8 CVI patients and 1 case of congenital agammaglobulinemia). No correlation was found between IFN production and natural killer activity in individual patients. The analysis of lymphocyte subsets by monoclonal antibodies revealed gross imbalances of helper/inducer and suppressor/cytotoxic subpopulations, but no overall correlation could be established with gamma-IFN production. The observation of major defects in gamma-IFN yield only in diseases with depression of T cell-mediated immunity might contribute to a better understanding of the pathogenetical mechanisms in these diseases. Moreover, future studies should monitor thesein vitro functions and their modifications byin vitro orin vivo manipulations.     

Structure-function effects in primary immunodeficiencies

Several immunodeficiency-related genes have been identified and a large number of mutations in these genes. Currently, a genetic defect has been determined in more than 2000 patients. Only recently has it become possible to address structure-function effects of these mutations in the corresponding proteins. The consequences of mutations in structure are discussed for Btk in X-linked agammaglobulinemia (XLA), Jak3 in T-B+ severe combined immunodeficiency (SCID), p47phox and p67phox in autosomal chronic granulomatous disease (CGD) and SH2D1 A in X-linked lymphoproliferatine disease (XLP). The experimental and homology modelling derived structures were used to analyze mechanisms related to these diseases.     

Gene therapy in primary immunodeficiencies

Primary immunodeficiencies are a group of disorders that are highly amenable to gene therapy due to their defined molecular biology and pathophysiology. The development of this new therapeutic modality has been driven by the established morbidity and mortality associated with conventional allogeneic stem cell transplantation, particularly in the human leukocyte antigen-mismatched setting. Recently, several clinical studies have demonstrated that conventional gene transfer technology can produce major beneficial therapeutic effects, but as for all cellular and pharmacologic treatment approaches, with a finite potential for toxicity. New strategies to overcome these issues are likely to establish gene therapy as an efficacious strategy for many forms of primary immunodeficiencies.     

Long-term follow-up of patients with primary immunodeficiencies

As an example of the need for long-term follow-up by specialty health care to adequately manage immunodeficient patients, we report the case of a patient with Wiskott-Aldrich syndrome who was lost to follow-up for 4 years to the immunology clinic and came back with a neck mass that was diagnosed as B-cell lymphoma. Patients with immunodeficiency are at high risk for the development of malignancy and autoimmune diseases and should be evaluated by a trained specialist with a frequency of not less than every 6 months.     

Stem cell transplantation in primary immunodeficiencies

PURPOSE OF REVIEW: To review indications and outcomes of haematopoietic stem cell transplantation in primary immunodeficiencies, in light of recent advances in the field. RECENT FINDINGS: Remarkable improvements in the outcome of haematopoietic stem cell transplantation in primary immunodeficiencies have recently been reported. This is a result of the successful use of alternative donors and more effective strategies to prevent and treat complications. These advances have now permitted the indications for haematopoietic stem cell transplantation to be extended in primary immunodeficiencies. SUMMARY: The optimal results of haematopoietic stem cell transplantation in primary immunodeficiencies have long been obtained with related human leukocyte antigen-identical donors, an option limited to a minority of patients. Transplantation from mismatched related donors has been used with good results mainly in infants with severe combined immune deficiency, but has been associated with significantly delayed or incomplete immune reconstitution. Recent data indicate that transplantation from matched unrelated donors and cord blood transplantation represent valid alternatives, which can be used in all forms of severe primary immunodeficiencies. This, along with careful monitoring of infections, coupled with preemptive treatment, has resulted in a significant improvement in the outcome of haematopoietic stem cell transplantation for severe forms of primary immunodeficiencies.     

Subcutaneous immunoglobulin replacement in primary immunodeficiencies

The use of small portable pumps for subcutaneous infusion of IgG in patients with primary immunodeficiencies was introduced more than 20 years ago. In the US, i.v.i.g. became more popular, but in other countries, many patients use the subcutaneous route. Pharmacokinetics of IgG differ when smaller doses are given more frequently, as is commonly done with subcutaneous regimens, as compared to the large boluses given every 21-28 days in most i.v. regimens. Differences include lower peaks and higher troughs, which may be preferable for some patients. Advantages of the subcutaneous route include increased patient autonomy, decreased systemic adverse effects, and the lack of a requirement for vascular access. Disadvantages include limitation in the volume that can be administered at any one time, necessitating frequent dosing; and the requirement for reliability if a patient is to self or home infuse. Obstacles may be encountered because no preparation of IgG is currently licensed for subcutaneous use in the US. Subcutaneous IgG replacement may be preferable to i.v. infusions or i.m. injections for carefully selected patients.     

Infectious pathogens in pediatric patients with primary immunodeficiencies.

BACKGROUND AND PURPOSE: Primary immunodeficiency diseases (PIDs) are rare disorders. Unusual infections often guide the initial investigation for immunodeficiency. METHODS: In order to ascertain the organisms that lead to a predisposition for PIDs, we reviewed the charts of 92 children diagnosed with PIDs at the National Taiwan University Hospital between March 1984 and March 2004. RESULTS: Pneumonia was diagnosed in 92%, 81%, and 76.5% of patients with antibody, combined, and cellular deficiencies, respectively. Other major illnesses were similar in the 3 groups and included bronchiolitis, acute gastroenteritis, otitis media, and bacteremia. Skin abscess, pneumonia, and lymphadenitis (54.5%, 45%, and 27% of cases, respectively) were the most common infections in patients with phagocyte defects. Organisms were speciated in only 44.8% of infection episodes. Most viral infections were diagnosed by traditional and time-consuming viral culture. Prophylactic antibiotics were prescribed to 9 out of the 92 patients with PIDs. CONCLUSIONS: Early recognition of PIDs requires that practitioners be aware of the infection characteristics, and subsequent reliable and rapid molecular diagnosis are needed in such immunocompromised patients.     

B cell development and primary immunodeficiencies with hypogammaglobulinemia

The differentiation of B cells along the pathway of B cell development has been well characterized. In the bone marrow, the differentiation from pro-B cells to immature B cells can be defined by several surface antigens, such as a surrogate light chain. Immature B cells become mature B cells and then circulate in the peripheral blood as naive B cells. In the peripheral lymphoid tissues, naive B cells differentiate into memory B cells, which express the CD27 molecule, or plasma cells. Primary immunodeficiencies with hypogammaglobulinemia are caused by defects of the specific molecules which are needed for the B cell differentiation. Recent studies of the genes responsible for such immunodeficiencies have clarified B cell development as well as their pathogenesis. We discuss here the molecules affecting the B cell development and primary immunodeficiencies with hypogammaglobulinemia.     

Gene therapy for primary immunodeficiencies

Gene therapy has effectively entered Medicine via the field of primary immunodeficiencies (PID). Because hematopoietic stem cells are accessible and because it was understood that genetic correction of lymphocyte progenitor cells carrying a genetic defect impairing differentiation, could result in the production of long‐lived T lymphocytes, it was reasoned that ex vivo gene transfer in hematopoietic cells could lead to disease phenotype correction. Retroviral vectors were designed to ex vivo transduce such cells. This has indeed been shown to lead to sustained correction of the T cell immunodeficiency associated with two forms of severe combined immunodeficiencies (SCID) for now more than ten years. Occurrence in some patients of genotoxicity related to retroviral vectors integration close to and transactivation of oncogenes has led to the development of retroviral vectors devoid of its enhancer element. Results of recent trials performed for several forms of PID indeed suggest that their use is both safe and efficacious. It is thus anticipated that their application to the treatment of many more life threatening PID will be developed over the coming years.