Disseminated Mycobacterium simiae infection in a patient with adult-onset immunodeficiency due to anti-interferon-gamma antibodies - a case report.

BACKGROUND: Mycobacterial species other than Mycobacterium tuberculosis and Mycobacterium leprae are generally free-living organisms and Mycobacterium simiae is one of the slowest growing Non-tuberculous mycobacteria. This is the first case report of Mycobacterium simiae infection in Sri Lanka and only very few cases with extrapulmonary manifestation reported in the literature. CASE PRESENTATION: A 24-year-old, previously healthy Sri Lankan male presented with generalized lymphadenopathy with discharging sinuses, evening pyrexia, weight loss, poor appetite and splenomegaly. Lymph node biopsies showed sheets of macrophages packed with organisms in the absence of granulomata. Ziehl Neelsen, Wade Fite and Giemsa stains revealed numerous red coloured acid-fast bacilli within foamy histiocytes. Slit skin smear for leprosy was negative and tuberculosis, fungal and bacterial cultures of the lymph node and bone marrow did not reveal any growth. Later he developed watery diarrhea and colonoscopy revealed multiple small polyps and ulcers throughout the colon extending up to the ileum, Which was confirmed to be due to cytomegalovirus confirmed by PCR and successfully treated with ganciclovir. Positron emission tomography scan guided biopsies of the gut and lymph nodes confirmed presence of mycobacterial spindle cell pseudo-tumours and PCR assays revealed positive HSP65. The culture grew Mycobacterium Simiae. Flow cytometry analysis on patient's blood showed extremely low T and B cell counts and immunofixation revealed low immunoglobulin levels. His condition was later diagnosed as adult onset immunodeficiency due to anti- interferon - gamma autoantibodies. He was initially commenced on empirical anti-TB treatment with atypical mycobacterial coverage. He is currently on a combination of daily clarithromycin, ciprofloxacin, linezolid with monthly 2 g/kg/intravenous immunoglobulin to which, he had a remarkable clinical response with complete resolution of lymphadenopathy and healing of sinuses. CONCLUSIONS: This infection is considered to be restricted to certain geographic areas such as mainly Iran, Cuba, Israel and Arizona and this is the first case report from Sri lanka. Even though the infection is mostly seen in the elderly patients, our patient was only 24 years old. In the literature pulmonary involvement was common presentation, but in this case the patient had generalized lymphadenopathy and colonic involvement without pulmonary involvement.

BCG: a vaccine with multiple faces.

BCG has been recommended because of its efficacy against disseminated and meningeal tuberculosis. The BCG vaccine has other mechanisms of action besides tuberculosis protection, with immunomodulatory properties that are now being discovered. Reports have shown a significant protective effect against leprosy. Randomized controlled trials suggest that BCG vaccine has beneficial heterologous (nonspecific) effects on mortality in some developing countries. BCG immunotherapy is considered the gold standard adjuvant treatment for non-muscle-invasive bladder cancer. BCG vaccine has also been tested as treatment for diabetes and multiple sclerosis. Erythema of the BCG site is recognized as a clinical clue in Kawasaki disease. BCG administration in the immunodeficient patient is associated with local BCG disease (BCGitis) or disseminated BCG disease (BCGosis) with fatal consequences. BCG administration has been associated with the development of autoimmunity. We present a brief review of the diverse facets of the vaccine, with the discovery of its new modes of action providing new perspectives on this old, multifaceted and controversial vaccine.

Recent advances in primary immunodeficiencies: identification of novel genetic defects and unanticipated phenotypes.

Primary immunodeficiencies (PIDs) have traditionally been defined according to their immunologic phenotype. Far from being concluded, the search for human genes that, when mutated, cause PID is actively being pursued. During the last year, four novel genetic defects that cause severe combined immunodeficiency and severe congenital neutropenia have been identified. At the same time, the immunologic definition of primary immunodeficiencies has been expanded by the recognition that genetic defects affecting innate immunity may result in selective predisposition to certain infections, such as mycobacterial disease, herpes simplex encephalitis, and invasive pneumococcal infections. Studies of genetically determined susceptibility to infections have recently shown that immunologic defects may also account for novel infectious phenotypes, such as malaria or leprosy. Finally, a growing body of evidence indicates that primary immunodeficiencies may present with a noninfectious clinical phenotype that may be restricted to single organs, as in the case of atypical hemolytic uremic syndrome or pulmonary alveolar proteinosis. Overall, these achievements highlight the importance of human models, which often differ from the corresponding animal models.

Revisiting human primary immunodeficiencies.

Human primary immunodeficiencies (PIDs) are often thought to be confined to a few rare, familial, monogenic, recessive traits impairing the development or function of one or several leucocyte subsets and resulting in multiple, recurrent, opportunistic and fatal infections in infancy. We highlight here the rapidly growing number of exceptions to each of these conventional qualifications. Indeed, bona fide PIDs include common and sporadic illnesses and may present as dominant, or even polygenic traits; their pathogenesis may involve non haematopoietic cells, and they may result in single episode of illness, with a single or multiple morbid phenotypes, some of which may involve infection, in otherwise healthy adults. We need to increase awareness of the multitude of clinical presentations of human PIDs considerably and rapidly in the medical community. Human PIDs should be considered in a wide range of clinical situations.

Genetic dissection of immunity to mycobacteria: the human model.

Humans are exposed to a variety of environmental mycobacteria (EM), and most children are inoculated with live Bacille Calmette-Guérin (BCG) vaccine. In addition, most of the world's population is occasionally exposed to human-borne mycobacterial species, which are less abundant but more virulent. Although rarely pathogenic, mildly virulent mycobacteria, including BCG and most EM, may cause a variety of clinical diseases. Mycobacterium tuberculosis, M. leprae, and EM M. ulcerans are more virulent, causing tuberculosis, leprosy, and Buruli ulcer, respectively. Remarkably, only a minority of individuals develop clinical disease, even if infected with virulent mycobacteria. The interindividual variability of clinical outcome is thought to result in part from variability in the human genes that control host defense. In this well-defined microbiological and clinical context, the principles of mouse immunology and the methods of human genetics can be combined to facilitate the genetic dissection of immunity to mycobacteria. The natural infections are unique to the human model, not being found in any of the animal models of experimental infection. We review current genetic knowledge concerning the simple and complex inheritance of predisposition to mycobacterial diseases in humans. Rare patients with Mendelian disorders have been found to be vulnerable to BCG, a few EM, and M. tuberculosis. Most cases of presumed Mendelian susceptibility to these and other mycobacterial species remain unexplained. In the general population leprosy and tuberculosis have been shown to be associated with certain human genetic polymorphisms and linked to certain chromosomal regions. The causal vulnerability genes themselves have yet to be identified and their pathogenic alleles immunologically validated. The studies carried out to date have been fruitful, initiating the genetic dissection of protective immunity against a variety of mycobacterial species in natural conditions of infection. The human model has potential uses beyond the study of mycobacterial infections and may well become a model of choice for the investigation of immunity to infectious agents.

Deficiencia selectiva de inmunoglobulina y enfermedades reumáticas inflamatorias / Selective deficience of immunoglobulin and inflammatory rheumatic diseases

La deficiencia selectiva de inmunoglobulina A (IgA) es la más frecuente de las inmunodeficiencias primarias e incluye individuos que sufren de infecciones respiratorias recurrentes, enfermedad diarreica crónicas y síndromes autoinmunes. En este estudio describimos la patología reumática inflamatoria que en nuesto medio se asocia a esta inmunodeficiencia. Durante los años 1977-1995 se detectaron dos casos de insuficiencia total y cinco de insuficiencia parcial de IgA. Los pacientes con insuficiencia total padecían de artritis reumatoide seronegativa el 1er caso y de enfermedad de Still del adulto y osteoartrosis erosiva el 2do caso; aquellos con insuficiencia parcial presentaban: lupus eritomatoso sistémico, anemia hemolítica secundaria y exoftalmos unilateral (caso No.1); enfermedad mixta del tejido conjuntivo (caso No.2); síndrome de Sjogren y lepra (caso No.3) y artritis reumatoide juvenil de inicio oligoarticular (casos No.4 y 5)

Analysis of immunoglobulin deficiency cases: a five year study.

A total of 734 serum specimens from various clinical disorders along with 100 control samples from healthy subjects were processed for estimation of serum IgG, IgA and IgM employing single radial immunodiffusion procedure. Immunoglobulin deficiency, either selective or combined was noted in 31 males and 24 females in all age groups. Of the 55 cases encountered it was secondary immunoglobulin deficiency which was seen on a larger scale and encountered in patients with Multiple myeloma (16 out of 32) followed by Leprosy (14 out of 250), Lymphoma (5 out of 43), Malaria (4 out of 137), Burns (4 out of 52), Rheumatoid arthritis (2 out of 69) and non lymphoreticular malignancies (1 out of 41) in decreasing order of frequency. Primary immunoglobulin deficiency was observed in nine cases comprising of six belonging to Idiopathic late onset immunoglobulin deficiency, two of dysgammaglobulineamia and a solitary case of Ataxia telangiectasia. Panimmunoglobulin deficiency was observed in six cases, 11 had a dual deficiency while 38 showed deficiency of an isolated class with selective IgA deficiency in 20 cases. Furthermore, one patient each had total absence of IgG or IgA while IgM was not detectable in seven patients. A high suspicion index along with a regular rapport between the clinician and the laboratory personnel is necessary in the diagnostic set up of immunoglobulin deficiency states.

Chronic mucocutaneous candidiasis with deficient CD2 (E receptor) but normal CD3 mononuclear cells.

A case of chronic mucocutaneous candidiasis in a Malaysian child who subsequently developed disseminated tuberculosis and toxoplasmosis is described. The phenotype of her peripheral blood mononuclear cells showed discordance for her T cell markers. The presence of a subpopulation of CD2-/CD3+ mononuclear cells leading to an immunodeficiency state is consistent with failure of activation of CD2-mediated alternative pathway resulting in immunodeficiency. Such abnormal CD2-/CD3+ subpopulations have been described in lepromatous leprosy and foetal abortuses.

[The modelling of chronic infection (experimental leprosy) against a background of macrophagal immunodeficiency]. / Modelirovanie khronicheskoi infektsii (éksperimental'noi lepry) na fone makrofagal'nogo immunodefitsita.

The dynamics of mycobacterial multiplication was followed in mice with intraplantar leprosy infection and preinduced macrophage insufficiency. The characteristics of Shepard's model appeared to be similar to those of the method proposed by the authors including the susceptibility to the main antileprosy drugs. Peritoneal macrophages were cytochemically studied in the process of development of mononuclear phagocyte deficiency and experimental leprosy. It was concluded that the method proposed preserving all the merits of Shepard's model should allow one to shorten significantly the duration of testing potential drugs for their antileprosy activity.

The alternative pathway of T cell activation: biology, pathophysiology, and perspectives for immunopharmacology.

The application of monoclonal antibodies and recombinant mediators to studies of T cell activation has led to a new concept regarding the central mechanisms underlying specific immune responses in man. Stimulation of human T cells to express their functional programs with regard to immunoregulatory activities and effector functions can be mediated through several distinct mechanisms or pathways. We report on the recently discovered T3-Ti antigen receptor independent mode of human T cell activation, namely, the T11-mediated "alternative pathway." Recent evidence supports the notion that this pathway plays an important role in the immune response in man and that failure to activate T cells through T11 is associated with immunodeficiency. The characterization of functional epitopes of the T11 molecule along with functional investigations on patients suffering from etiologically different cases of immunodeficiency provides important perspectives for future pharmacological interventions into the human immune system. It seems likely that immunologic disorders such as autoimmune disease and immunodeficiencies result from overamplification or blockades of the "alternative pathway of T cell activation" and that the T11 epitope represents a potential site for selective inhibition of the "alternative pathway of T cell activation," e.g., by means of synthetic peptide analogues. Conversely, high affinity ligands to the T11 epitope might be suitable for immunostimulation immunodeficiencies that result from circulating blocking factors of the LFA-3/T11 interaction.

[Reproduction of experimental leprous infection in mice with a preliminary modelling of failure of the mononuclear phagocyte system]. / Vosproizvedenie éksperimental'noi leproznoi infektsii u myshei s predvaritel'no modelirovannoi nedostatochnost'iu sistemy mononuklearnykh fagotsitov.

CBA mice with induced insufficiency of mononuclear phagocyte system (MNPS) were inoculated intraplantar with M. leprae in a dose of 1 X 10(4). A significantly accelerated multiplication of M. leprae was noted in the sites of inoculation with the development of a generalized infections process and appearance in 6 months after inoculation of lepromatous structures in spleen, liver and other internal organs as compared with the animals with unchanged MNPS. The data obtained suggest that insufficiency in macrophage component of cell-mediated immunity might underline the sensibility to leprosy infection.

Mechanisms of Mycobacterium leprae-specific T-cell deficiency in lepromatous leprosy.

Patients suffering from lepromatous leprosy fail to develop an efficient cell-mediated immunity towards Mycobacterium leprae, the causative agent. The mechanism of such a specific T-cell tolerance to the bacillus remains a key question in the pathophysiology of leprosy. Macrophages do not show any intrinsic defect in phagocytizing and killing M. leprae or in presenting antigen to helper T-cells. On the other hand, M. leprae-reactive helper T-cells do persist in lepromatous patients, but their activation appears to prevented by active suppressor mechanisms, involving both suppressor T-cells and macrophages. The target of this specific suppression could be the interleukin 2-producing T-cell subset. A better molecular definition of M. leprae antigens, both by monoclonal antibodies and T-cell clones, should open new perspectives for further analysis of the regulation of immune responses to M. leprae.

Defective activation of granuloma macrophages from Mycobacterium leprae-infected nude mice.

We have previously demonstrated that granuloma macrophages from the foot pads of Mycobacterium leprae-infected nude mice are functionally normal despite heavy intracellular burdens of bacilli. However, unlike peritoneal macrophages, these macrophages fail to restrict the intracellular growth of Toxoplasma gondii when stimulated with recombinant murine gamma interferon (Mu IFN-gamma) and thus appear defective in their response to macrophage-activating factor(s). In further characterizing this defect we have examined tumoristatic capacity, superoxide radical formation, and expression of la antigens on granuloma macrophages before and after treatment with Mu IFN-gamma. By all three criteria, M. leprae-burdened granuloma macrophages failed to become activated by doses of Mu IFN-gamma that readily activate peritoneal macrophages from M. leprae-infected nude mice or normal Balb/c mice. M. leprae-infected granuloma macrophages produced elevated levels of prostaglandin E2 (PGE2) in vitro, which was suppressed by indomethacin. However, the inhibition of PGE2 production for 48 hr in vitro did not restore normal responses to Mu IFN-gamma.

Renal involvement in Mycobacterium leprae infected mice. Histopathological, bacteriological and immunofluorescence study.

Swiss albino mice were inoculated in the footpads with Mycobacterium leprae obtained from untreated lepromatous patient. The kidneys obtained from the animals sacrificed during different periods were processed for histopathology, presence of AFB and immunofluorescence studies. Renal lesions, AFB and immune complex deposits were seen in the infected animals. Such findings have not been studied in great detail in experimental leprosy earlier.