Precipitins to candida albicans in chronic mucocutaneous candidiasis studied by crossed immunoelectrophoresis with intermediate gel. Correlation with clinical and immunological findings

The precipitating antibodies in the sera of fifteen patients with chronic mucocutaneous candidiasis were examined by crossed immunoelectrophoresis with intermediate gel. The method permitted identification and quantitation of precipitins against thirty-four of the seventy-eight known antigenic components of Candida albicans.

The sera from every patient contained precipitins and the number of reactivities per serum ranged from two to thirty-nine. All patients had antibodies to antigen 78, a mannan–protein complex. Many sera also possessed antibodies to many other components of the organism, suggesting that some of the yeast cells had been disrupted in the patients' tissues. However, there were no precipitin profiles that characterized patients with specific forms of chronic candidiasis. Instead, in two cases, the antibody profiles appeared to be related to the patients' ability to develop humoral immune responses. Serial studies of patients during remissions and exacerbations showed that there were no consistent changes in antibody activities.

The role of Candida precipitins in chronic candidiasis remains uncertain. Possible functions include prevention of dissemination of the infection from superficial sites, formation of immune complexes in superficial sites and suppression of cell-mediated immunity as suggested by in vitro tests.

     

Autoimmune hemolytic anemia in chronic mucocutaneous candidiasis.

Chronic mucocutaneous candidiasis is an immunodeficiency disease characterized by T-cell dysregulation and chronic superficial candidal infections. We report on three patients with chronic mucocutaneous candidiasis who developed autoantibodies to erythrocytes. Our first patient, a 19-year-old female, developed autoimmune hemolytic anemia (AIHA) that required multiple courses of treatment, including corticosteroids, intravenous immunoglobulin, and danazol. During the last exacerbation of AIHA, intensive treatment with corticosteroids and intravenous immunoglobulin failed and yet the patient responded to plasmapheresis. Our second patient, a 21-year-old male, developed AIHA which responded to oral corticosteroid therapy. Our third patient, a 6-year-old female without evidence of hemolysis, was found to have erythrocyte autoantibodies on routine screening. These three patients had positive direct antiglobulin tests, and the first patient had both immunoglobulin G (IgG) and IgM erythrocyte autoantibodies, while the remaining two patients had only IgG autoantibody. This is the first report of the association of AIHA with chronic mucocutaneous candidiasis. We suggest that all patients with chronic mucocutaneous candidiasis be screened periodically for erythrocyte autoantibodies. Plasmapheresis, a safe ancillary procedure in the management of AIHA, may be life-saving in some cases. The occurrence of erythrocyte autoantibodies in mucocutaneous candidiasis may be related to immunoregulatory disorders in this disease.     

Numerical and functional deficiency in T helper cells in protein energy malnutrition

Protein energy malnutrition decreased the number of rosette forming T lymphocytes, of T4 positive cells and their ability to provide help to B cells in antibody synthesis. There was a reduction in serum thymic hormone activity and an elevation of leucocyte terminal transferase and plasma cortisol levels. The numberical and functional deficiency of T4⁺ helper cells may be important in the pathogenesis of some of the clinical and immunological manifestations of protein energy malnutrition.     

Chronic mucocutaneous candidiasis,a case study and literature review

Chronic mucocutaneous candidiasis (CMC) is a clinically heterogeneous disease. Some immunologic and hormonal abnormalities have been associated with CMC. The factors that predispose host to CMC infection could be autosomal or acquisitive. The disease usually occurs in childhood. Here, we reviewed the published literature on chronic mucocutaneous candidiasis and a four years old girl is presented with CMC. She had a history of recurrent thrush and otomycosis since the age of one. Candida albicans was detected in skin scraping and biopsy samples. Serum iron was low. TSH hormone level was high and T4 level was low. Giardia cysts were found in stool sample. Mucocutaneous and nail manifestations of the disease were disappeared after a period of Itraconazole therapy.     

Mucocutaneous candidiasis and autoimmunity against cytokines in APECED and thymoma patients: clinical and pathogenetic implications

Much has been learnt about the mechanisms of thymic self-tolerance induction from work on both the rare autosomal recessive disease autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) and the autoimmune regulator (AIRE) protein mutated in this disease. Normally, AIRE drives low-level expression of huge numbers of peripheral tissue-specific antigens (TSAgs) in medullary thymic epithelial cells (mTECs), leading to the deletion of TSAg-reactive thymocytes maturing nearby. The very recently discovered neutralizing autoantibodies (autoAbs) against Th17-related cells and cytokines in two autoimmunity-related syndromes associated with AIRE-mutant thymi or AIRE-deficient thymomas help to explain the chronic mucocutaneous candidiasis (CMC) seen in both syndromes. The surprising parallels between these syndromes also demand new hypotheses and research into the consequences of AIRE deficiency and the ensuing autoimmunizing pathways, and suggest more appropriate treatment regimens as discussed in this review.     

Anti‐cytokine autoantibodies suggest pathogenetic links with autoimmune regulator deficiency in humans and mice

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a recessive disorder resulting from mutations in the autoimmune regulator (AIRE). The patients' autoantibodies recognize not only multiple organ‐specific targets, but also many type I interferons (IFNs) and most T helper type 17 (Th17) cell‐associated cytokines, whose biological actions they neutralize in vitro. These anti‐cytokine autoantibodies are highly disease‐specific: otherwise, they have been found only in patients with thymomas, tumours of thymic epithelial cells that fail to express AIRE. Moreover, autoantibodies against Th17 cell‐associated cytokines correlate with chronic mucocutaneous candidiasis in both syndromes. Here, we demonstrate that the immunoglobulin (Ig)Gs but not the IgAs in APECED sera are responsible for neutralizing IFN‐ω, IFN‐α2a, interleukin (IL)‐17A and IL‐22. Their dominant subclasses proved to be IgG1 and, surprisingly, IgG4 without IgE, possibly implicating regulatory T cell responses and/or epithelia in their initiation in these AIRE‐deficiency states. The epitopes on IL‐22 and IFN‐α2a appeared mainly conformational. We also found mainly IgG1 neutralizing autoantibodies to IL‐17A in aged AIRE‐deficient BALB/c mice – the first report of any target shared by these human and murine AIRE‐deficiency states. We conclude that autoimmunization against cytokines in AIRE deficiency is not simply a mere side effect of chronic mucosal Candida infection, but appears to be related more closely to disease initiation.     

Chronic mucocutaneous candidiasis

Chronic mucocutaneous candidiasis can be defined as a group of syndromes that have as a common feature infections of the skin, nails and mucous membranes withCandida albicans. A variety of disorders including endocrine dysfunctions, alopecia, vitiligo, malabsorption syndromes, neoplasms and other infections may also occur in patients with chronic mucocutaneous candidiasis, but these vary considerably from patient to patient. In most patients with chronic mucocutaneous candidiasis, there are abnormalities of cell-mediated immunity. These may be limited to antigens ofCandida albicans, but in some patients they are more extensive and involve the T-lymphocyte-mediated responses to all antigens. These immunulogic defects are the factors that predispose patients to infections with opportunistic organisms such asCandida spp. Fungal infections in patients with chronic mucocutaneous candidiasis usually respond to treatment with conventional antifungal agents, but often relapse shortly after treatment is stopped unless the defects in the cell-mediated immune system have been corrected.     

Chronic mucocutaneous candidiasis and systemic lupus erythematosus: a new variant of chronic mucocutaneous candidiasis?

Chronic mucocutaneous candidiasis (CMC) is characterized by susceptibility to Candida infection of skin, nails, and mucous membranes. Autoimmune endocrinopathies are common in CMC patients, but there are no reports of the involvement of systemic autoimmune disorders. We present here the first case of this kind of association in a patient with an autosomal dominant variant of CMC. The individual had had this disorder since childhood and systemic lupus erythematosus with secondary antiphospholipid syndrome, as well as renal, articular and hepatic manifestations without thymoma.     

Treatment of chronic mucocutaneous moniliasis by immunologic reconstitution

The immunological defect in a patient with chronic mucocutaneous moniliasis was characterized. While his Candida skin test was negative. exposure of his lymphocytes to candida extracts in vitro produced an increase in thymidine incorporation. Supernatants from cultures of antigen-stimulated lymphocytes did not contain macrophage migration-inhibition factor (MIF) activity.

Restoration of the immune system with transfusions of immuno-competent allogeneic lymphocytes was accompanied by conversion of the Candida skin test to positive, and MIF production by his lymphocytes. During the period that his immune system remained intact, there was marked clearing of the moniliasis. Eight months following the transfusions, the moniliasis recurred and when restudied, the patient again had negative skin tests and insignificant MIF production.

These observations demonstrate the importance of mediators in the expression of delayed hypersensitivity and provide evidence of a role of cellular immunity in resistance to certain chronic fungal infections.

     

Serum thymic hormone activity in protein-energy malnutrition.

To characterize the underlying mechanisms of impaired cell-mediated immunity in protein-energy malnutrition, thymic hormone activity was measured in the serum samples of undernourished children and was found to be reduced in the majority. This indicates that the cellular immunological deficit in nutritional deficiency may be due to reduced thymic inductive activity.     

Autologous Mixed Lymphocyte Reaction in Man

The autologous mixed lymphocyte reaction (AMLR) and T-cell subsets defined with monoclonal antibodies were examined in the peripheral blood of six patients with chronic mucocutaneous candidiasis (CMC). The AMLR was deficient in four of six patients when compared with simultaneously studied healthy controls. These patients had either overt endocrinopathy or circulating autoantibodies. In two of three patients with low AMLR, after the depletion of OKT8+ T cells no enhancement in the AMLR was observed, demonstrating that the deficiency of the AMLR was not due to increased suppressor OKT8+ T-cell activity. However, the third patient demonstrated almost complete reconstitution of the AMLR response after such depletion, suggesting that OKT8+ suppressor T cells were responsible for decreased AMLR in this patient. Two patients had a low ratio of OKT4/OKT8 phenotype T cells. T cells with Tac antigen (that is, present on activated T cells) were increased in four of six patients. No correlation was observed between the deficiency of the AMLR and the proportions of T-cell subsets. This study demonstrates a deficiency of the AMLR in some patients with CMC which is associated with increased OKT8+ suppressor T-cell activity or with the functional deficiency of responder OKT4+ T cells.     

A serum-dependent defect of neutrophil function in chronic mucocutaneous candidiasis.

Investigations into the immunological functions of three patients with chronic mucocutaneous candidiasis were carried out. Phagocytosis of Candida albicans, nitroblue tetrazolium dye reduction, complement, and immunoglobulin levels were normal. Candidacidal assays using the neutrophils of the patients in autologous serum showed significant decreases below normal levels. This decrease in kill could be corrected by incubating the patients' cells in normal control or human AB serum. Cross-over serum studies also showed that the patients' sera had inhibitory effects on the candidacidal capacity of normal neutrophils. These changes in kill were related to candida antibody levels.     

Genetic Analysis of a Cohort of 275 Patients with Hyper-IgE Syndromes and/or Chronic Mucocutaneous Candidiasis

Hyper-IgE syndromes and chronic mucocutaneous candidiasis constitute rare primary immunodeficiency syndromes with an overlapping clinical phenotype. In recent years, a growing number of underlying genetic defects have been identified. To characterize the underlying genetic defects in a large international cohort of 275 patients, of whom 211 had been clinically diagnosed with hyper-IgE syndrome and 64 with chronic mucocutaneous candidiasis, targeted panel sequencing was performed, relying on Agilent HaloPlex and Illumina MiSeq technologies. The targeted panel sequencing approach allowed us to identify 87 (32 novel and 55 previously described) mutations in 78 patients, which generated a diagnostic success rate of 28.4%. Specifically, mutations in DOCK8 (26 patients), STAT3 (21), STAT1 (15), CARD9 (6), AIRE (3), IL17RA (2), SPINK5 (3), ZNF341 (2), CARMIL2/RLTPR (1), IL12RB1 (1), and WAS (1) have been detected. The most common clinical findings in this cohort were elevated IgE (81.5%), eczema (71.7%), and eosinophilia (62.9%). Regarding infections, 54.7% of patients had a history of radiologically proven pneumonia, and 28.3% have had other serious infections. History of fungal infection was noted in 53% of cases and skin abscesses in 52.9%. Skeletal or dental abnormalities were observed in 46.2% of patients with a characteristic face being the most commonly reported feature (23.1%), followed by retained primary teeth in 18.9% of patients. Targeted panel sequencing provides a cost-effective first-line genetic screening method which allows for the identification of mutations also in patients with atypical clinical presentations and should be routinely implemented in referral centers.

     

Mannan-specific and mannan-induced T-cell suppressive activity in patients with chronic mucocutaneous candidiasis

We have studied T- and B-cell responses to antigens ofCandida albicans in 18 patients suffering from chronic mucocutaneous candidiasis. We have shown thatin vitro production of antibody to one of these antigens, mannan, was absent during the active phase of the disease and that this absence was consequent to the activation of specific CD₈(+) and CD₈(–) suppressor T lymphocytes. Such activation was also observed when control T lymphocytes were incubated in the presence of monocytes and a high concentration of mannan. This suppressive effect was specific to antigens ofCandida albicans, was radiosensitive, and was not consequent to the secretion of prostaglandin E2. It appeared as well that the induction of these suppressor T cells was HLA-DQ restricted. The suppressor T-cell activity induced by antigens ofCandida albicans in vitro is thus comparable to the suppressor T-cell activity observedin vivo in patients affected with chronic mucocutaneous candidiasis. Defective handling of mannan by monocytes could result in the accumulation of mannan, resulting in the activation of specific T suppressor cells and in the consequent cellular immunodeficiency specific toCandida albicans. Successful treatment of the candidiasis resulted in complete correction of the immune abnormalities.     

Alteration of T cell function in healthy persons with a history of thymic x-irradiation.

The possible late effects of x-irradiation to the infantile thymus were investigated by studying immune functions in 12 healthy persons with a history of thymic x-irradiation and healthy control subjects. No differences were found in serum immunoglobulin values, humoral antibody levels, lymphocyte counts, and lymphocyte reactivity to phytochemagglutinin, vaccinia virus, purified protein derivative (PPD), and allogeneic cells. The irradiation group exhibited cellular hyperresponsiveness to streptoskinase-streptodornase (SK-SD). In contrast, mean skin and in vitro lymphocyte responses to Candida albicans were depressed in the patients with thymic irradiation. A dissociation of these two Candida responses was found in only 1 of 14 healthy control subjects but in 7 of 12 irradiated individuals. While thymic irradiation did not result in impaired immunologic defenses leading to clinical disease, it caused alterations in T cell responses similar to those reported in patients with chronic mucocutaneous candidiasis.     

In vitro effect of TP-1 (a calf thymic extract) on suppressor T-cell function of patients with autoimmune chronic active hepatitis

Concanavalin A-activated T-lymphocyte suppression of IgG production was found to be significantly impaired in patients with untreated active autoimmune chronic hepatitis when compared to normals or patients with inactive disease. When the dose-response effect of TP-1, a calf thymic extract, on in vitro suppressor cell activity was assessed, lymphocytes from six out of eight patients with previously reduced suppressor cell function showed a significant improvement, while over a similar range the suppressor cell activity of most normal controls declined. These results support the possibility that defective immunoregulation in patients with autoimmune chronic active hepatitis may be related to a deficiency in thymic hormone levels.     

Immunity to infection in IL-17-deficient mice and humans

Mice with defective IL-17 immunity display a broad vulnerability to various infectious agents at diverse mucocutaneous surfaces. In humans, the study of patients with various primary immunodeficiencies, including autosomal dominant hyper-IgE syndrome caused by dominant-negative STAT3 mutations and autosomal recessive autoimmune polyendocrinopathy syndrome type 1 caused by null mutations in AIRE, has suggested that IL-17A, IL-17F and/or IL-22 are essential for mucocutaneous immunity to Candida albicans. This hypothesis was confirmed by the identification of rare patients with chronic mucocutaneous candidiasis (CMC) due to autosomal recessive IL-17RA deficiency and autosomal dominant IL-17F deficiency. Heterozygosity for gain-of-function mutations in STAT1 in additional patients with CMC was recently shown to inhibit the development of IL-17 T cells. Although the infectious phenotype of patients with CMC and inborn errors of IL-17 immunity remains to be finely delineated, it appears that human IL-17A and IL-17F display redundancy for protective immunity in natural conditions that is not seen in their mouse orthologs in experimental conditions.     

Mucocutaneous candidiasis, anergy and a plasma inhibitor of cellular immunity: reversal after amphotericin B therapy

A patient with chronic mucocutaneous candidiasis and cutaneous anergy has been studied and found to have a circulating plasma factor capable of quenching in vitro lymphocyte responses of leucocytes of clinically well donors to monilia and other specific mitogenic stimulants. After instituting systemic amphotericin B therapy, the patient exhibited rapid clearing of cutaneous and mucosal lesions and the plasma inhibitor was no longer demonstrable. Loss of the plasma inhibitor was followed by appearance of strong cutaneous hypersensitivity and in vitro leucocyte responses to Candida albicans and streptococcal products. These clinical immunologic studies have pointed meaning in relationship to current views regarding immunologic reconstitution vis-à-vis systemic antifungal therapy in treatment of chronic candidiasis.     

Primary Immunodeficiency Disorders in the Republic of Ireland: First Report of the National Registry in Children and Adults

Data collection for the national registry for patients with primary immunodeficiency disorders in the Republic of Ireland commenced in 1996. One hundred and fifteen cases of primary immunodeficiency diseases were registered between December 1996 and February 2003. The most frequent primary immunodeficiency disorders were antibody deficiency (n = 53) and complement deficiency (n = 32). In addition, patients with T cell deficiency (n = 11) and chronic granulomatous disease (n = 11) were identified. A small number of patients with Wiskott–Aldrich syndrome, natural killer cell deficiency, DiGeorge syndrome and chronic mucocutaneous candidiasis were also registered. Comparison of our data with that recently reported in the European registry revealed that complement deficiency was more prevalent in the Republic of Ireland compared to other European countries. Results of our registry point to a significant prevalence of primary immunodeficiency disorders in the Republic of Ireland (2.9 cases per 100.000 population). However, it is likely that these figures underestimate the true prevalence of such cases in the country. We hope, with increased awareness of the national registry among primary care physicians, that more patients will be included and we will be able to identify accurately the frequency and the distribution of these disorders.