Asymptomatic persistent pulmonary infiltrates in an immunocompetent boy with cat-scratch disease.

We describe here an immunocompetent boy with fever, regional adenopathy, multifocal hepatosplenic granulomas, and high and increasing serum antibody titers for Bartonella henselae in whom diffuse bilateral reticulonodular pulmonary infiltrates developed in the absence of respiratory symptoms.

Transient beneficial effect of GH replacement therapy and topical GH application on skin ulcers in a boy with prolidase deficiency.

A diagnostic examination for short stature in a boy with chronic ulcers of the feet due to prolidase deficiency, a rare disorder associated with intractable ulcers of the skin, led to the diagnosis of growth hormone (GH) deficiency. Replacement treatment with r-hGH associated with the topical application of a GH-containing ointment when the boy was 13 years old resulted in complete but transitory healing of the ulcers, which can probably be attributed to the growth-promoting effects of GH on dermal connective tissue.

Increased frequency of RAG-expressing, CD4(+)CD3(low) peripheral T lymphocytes in patients with defective responses to DNA damage.

Accumulating evidence indicates that peripheral lymphocyte variants with altered antigen receptor expression may be capable of expressing recombination-activating genes (RAG). We and others recently observed functional RAG gene products in mature T cells with defective TCR expression (MacMahan and Fink, Immunity 1998. 9: 637 - 647; Lantelme et al., J. Immunol., 2000. 164: 3455 - 3459). Here, the association between TCR expression and RAG activity was assessed further in lymphocytes from patients with defective responses to DNA damage. We show that T cells with altered TCR surface expression are present in increased numbers in these patients and that they express RAG genes. The finding of RAG gene expression by TCR variants suggests the possibility that secondary V(D)J rearrangements could be induced in these cells to rescue their defective phenotype and cellular function. Moreover, as V(D)J recombination has been implicated in chromosome translocations involving antigen receptor genes, we discuss a possible relationship between altered TCR expression, RAG activity and the frequent lymphoma-specific translocations observed in these patients.

Cutting edge: recombinase-activating gene expression and V(D)J recombination in CD4+CD3low mature T lymphocytes.

The recombinase-activating genes, RAG-1 and RAG-2, can be expressed by a subset of B cells within germinal centers, where they mediate secondary V(D)J rearrangements. This receptor revision mechanism could serve either receptor diversification or tolerance-induced functions. Alternatively, it might rescue those cells the receptors of which have been damaged by somatic mutation. Less is known about the occurrence of similar mechanisms in T cells. Here we show that mature T cells with defective TCR surface expression can express RAG genes and are capable of initiating secondary V(D)J rearrangements. The possibility that a cell rescue mechanism based on the generation of a novel Ag receptor might be active in peripheral T cells is envisaged.

IL-10 and IL-4 co-operate to normalize in vitro IgA production in IgA-deficient (IgAD) patients.

In the present study we evaluated in vitro immunoglobulin production from IgAD individuals and healthy controls. Peripheral blood mononuclear cells (PBMC) from IgAD and controls were cultured with anti-CD40 MoAb presented on a CDw32-transfected fibroblast cell line (CD40 system) in the presence of IL-10, IL-2, IL-4, transforming growth factor-beta (TGF-beta) alone as well as of IL-10 in combination with each of the other three cytokines. Only IL-10 added alone induced significant changes in baseline immunoglobulin production; marked increases in median supernatant levels of all three isotypes were observed in both groups. The most striking finding of this study was the synergizing effect of IL-4 on IgA production in the IgAD group when added with IL-10; median IgA supernatant level increased to a value superimposable on that found in the normal controls which remained about the same as when stimulated with IL-10 alone. The synergic effect of IL-4 and IL-10 was specific to the IgA isotype.

Electrophysiologic study of central motor pathways in ataxia-telangiectasia.

To date, corticospinal tract functional integrity in ataxia-telangiectasia has not been studied. Thorough evaluation of central motor pathways is also lacking in neuropathologic and clinical studies. Using electromagnetic stimulation, we assessed the integrity of the corticospinal tracts in eight patients with ataxia-telangiectasia. Cortical and peripheral compound motor action potentials were recorded from the abductor pollicis brevis muscle. Recordings of the shortest F-wave latency and of the compound motor action potential distal latency were made from the abductor pollicis brevis muscle after electrical stimulation of the median nerve at the wrist. A significant increase in central motor conduction time was observed in four patients, two of whom had clinical findings compatible with a pyramidal lesion. This study demonstrates involvement of the central motor pathways in ataxia-telangiectasia, which appears to be more frequent late in the course of the disease.

Clinical spectrum of X-linked hyper-IgM syndrome.

We report the clinical and immunologic features and outcome in 56 patients with X-linked hyper-IgM syndrome, a disorder caused by mutations in the CD40 ligand gene. Upper and lower respiratory tract infections (the latter frequently caused by Pneumocystis carinii), chronic diarrhea, and liver involvement (both often associated with Cryptosporidium infection) were common. Many patients had chronic neutropenia associated with oral and rectal ulcers. The marked prevalence of infections caused by intracellular pathogens suggests some degree of impairment of cell-mediated immunity. Although lymphocyte counts and in vitro proliferation to mitogens were normal, a defective in vitro proliferative response to antigens was observed in some patients, and additional defects of cell-mediated immunity may be presumed on the basis of current knowledge of CD40-ligand function. All patients received regular infusions of immunoglobulins. Four patients underwent liver transplantation because of sclerosing cholangitis, which relapsed in there. Three patients underwent bone marrow transplantation. Thirteen patients (23%) died of infection and/or liver disease. X-linked hyper-IgM syndrome, once considered a clinical variant of hypogammaglobulinemia, is a severe immunodeficiency with significant cellular involvement and a high mortality rate.

Defective expression of HLA class I and CD1a molecules in boy with Marfan-like phenotype and deep skin ulcers.

We report the case of a boy with low expression of HLA class I molecules on peripheral blood mononuclear cells, which is associated with immunodeficiency. The patient, who had a Marfan-like phenotype, had chronic deep skin ulcers and sinobronchiectasis. Immunohistologic examination of the ulcerated skin showed a dense perivascular infiltrate composed of normal mature lymphocytes and macrophages. All cells in the infiltrate showed an apparently normal expression of HLA class I molecules, but intraepidermal dendritic Langerhans' cells were negative for CD1a, an antigen that is a highly specific marker for these cells and is abundantly expressed in some self-healing forms of cutaneous lesions. It is therefore speculated that a defective expression of CD1a molecules can contribute to the chronic persistence of deep skin ulcers, which have already been reported in association with defective expression of HLA class I molecules.

CD40lbase: a database of CD40L gene mutations causing X-linked hyper-IgM syndrome.

X-linked hyper-IgM syndrome (X-HIM) is an immunodeficiency caused by mutations in the gene encoding the CD40 ligand (CD40L). A database (CD40Lbase) of CD40L mutations has now been established, and the resultant information, together with other mutations reported elsewhere in the literature, is presented here.

Prevalence and diagnosis of celiac disease in IgA-deficient children.

BACKGROUND: Reported frequencies of celiac disease in selective IgA deficiency in childhood vary widely and this is probably due to the different characteristics of the patients studied and to the different criteria used for intestinal biopsy: all patients or only those with symptoms of malabsorption. Diagnosis of celiac disease is of considerable importance in IgA deficiency because of its increased frequency and also because avoidance of dietary gluten permits elimination of the symptoms and complications of celiac disease. OBJECTIVES: To obtain a more reliable estimate of the incidence of celiac disease in childhood IgA deficiency jejunal biopsies were performed in 65 consecutively diagnosed IgA-deficient children whose parents consented. Some clinical and laboratory parameters including IgA-antigliadin and IgG-antigliadin antibodies were evaluated to predict their usefulness in selecting IgA-deficient patients for intestinal biopsy. METHODS: All IgA-deficient patients had serum IgA levels below 5 mg/dL and salivary IgA below 0.5 mg/dL. Jejunal biopsy was performed using a peroral Watson capsule and IgA-antigliadin and IgG-antigliadin antibodies were performed by an ELISA assay. RESULTS: Biopsy findings of severe villous atrophy permitted diagnosis of celiac disease in 7.7% (5/65 children). IgG-antigliadin antibody levels, elevated in 16 patients including all five celiacs, were the best parameter for predicting celiac disease and gave no false negatives. CONCLUSIONS: The 7.7% frequency of celiac disease observed in these IgA-deficient children is about 20 times higher than in the general Italian population, and the lowest among the studies biopsying all patients; this is probably attributable to the presence of a substantial proportion of healthy children (20/65) and very few (2/65) with autoimmune disorders. The elevated sensitivity and negative-predictive value of IgG-antigliadin antibodies lead us to suggest that positive IgG-antigliadin antibodies can be used to select IgA-deficient children for jejunal biopsy with a very low probability of missing celiac disease while allowing a drastic reduction in the number of biopsies performed.

An unusual association: celiac disease and Becker muscular dystrophy.

A history of poor growth in early childhood associated with persistent diarrhea and iron deficiency anemia led to a diagnosis of celiac disease in a 9-yr-old boy hospitalized for acute rhabdomyolysis. Elevated serum creatine kinase levels had been documented over the previous years, and Becker's muscular dystrophy was diagnosed by immunostaining of dystrophin and DNA analysis.

Chronic tonsillitis in children: activation of polymorphonuclear cells from peripheral blood and tonsillar tissue. In vitro production of MPO, ECP and EPX.

Activation of polymorphonuclear cells (PMNs), neutrophils and eosinophils, occurs in response to infections. Myeloperoxidase (MPO) is an enzyme contained in neutrophils with toxic activity for many microorganisms including bacteria. Fosinophil cationic protein (ECP) and eosinophil X protein (EPX) are released by activated eosinophils in response to different inflammatory stimuli. Determination of serum levels of MPO, ECP and EPX permits assessment of the state of activation of these cells. The purpose of this study was to evaluate the state of activation of neutrophils and eosinophils present in tonsillar tissue and peripheral blood from 30 children (18 boys and 12 girls) undergoing tonsillectomy for chronic tonsillitis. For determination of serum levels of MPO, ECP and EPX, peripheral blood samples were obtained at the time of surgery: PMNs were separated by erythrosedimentation from peripheral blood and from tonsillar tissue after surgery and cultured for 7 days. The cells were plated (10(5) well) and the plates were incubated in 5% CO(2), 7% O(2), 80% N(2). After 2, 24, 48, 72, 96, 120, 144 h, supernatants were removed from the cultures of both tonsillar tissue and peripheral blood PMNs for determination of in vitro release of MPO, ECP and EPX. The assays were carried out using a radioimmunotechnique (RIA, Pharmacia) and the concentrations of the three proteins (mean/6 wells) for each time were expressed in mu g/l. The data suggest activation of PMNs in children with chronic tonsillitis.

Expansion of large granular lymphocyte subsets in Wiskott-Aldrich syndrome.

We describe a 9-year-old boy with Wiskott-Aldrich syndrome and IgM-rheumatoid factor-positive arthritis who presented expansion of two distinct subsets (one CD8dim and the other CD8-) of large granular lymphocytes. Natural killer activity against the K-562 cell line was absent. An increased percentage of CD5+ B cells was also observed. Since patients with Wiskott-Aldrich syndrome are at risk of developing autoimmune disorders - conditions in which increased CD5+ B cells have been observed - the high percentage of CD5+ B cells together with the presence of IgM-rheumatoid factor and anti-platelet antibodies may represent an early manifestation of an autoimmune process. The possible relationship between CD5+ B cells and large granular lymphocyte expansion is discussed.

Prolidase deficiency: biochemical study of erythrocyte and skin fibroblast prolidase activity in Italian patients.

BACKGROUND AND METHODS: Prolidase deficiency (PD), a rare, autosomally inherited disorder causing iminodipeptiduria is associated with a number of clinical manifestations, the principle feature being chronic skin ulceration. The enzyme prolidase cleaves iminodipeptides containing C-terminal prolyl or hydroxyprolyl residues and is important in the final stages of protein catabolism. We report clinical and biochemical findings in 8 Italian patients with proven prolidase deficiency. There was considerable heterogeneity in age at onset of symptoms (varying from 3-17 years), mental retardation and clinical manifestations (asymptomless to very severe). Prolidase activity was determined in hemolysates of patient erythrocytes and cultured dermal fibroblasts. RESULTS: Prolidase activity was found to be deficient, especially against gly-pro. Erythrocyte and fibroblast enzyme was also separated into two forms, a major isoform (I) and a minor one (II) by fast protein liquid chromatography, and activity against different iminodipeptide substrates was tested. Isoform I activity was markedly reduced in all patients as compared to normal controls, while isoform II activity appeared to be unaltered. CONCLUSIONS: We were unable to find any correlation between degree of enzyme activity loss and severity of symptoms.

[Phadiatop-Paediatric, a new screening test for atopy: a comparison with RAST results]. / Phadiatop-pediatrico, un nuovo test di screening per atopia: confronto con i risultati del RAST.

The results obtained using a new in vitro screening test for atopy Phadiatop-paediatric (Phad-P) and RAST for multiple food and inhalant allergens in 132 children (82 with atopic dermatitis and 50 with a negative history of atopic symptoms are compared. 64% of the subjects were RAST-positive for food allergens (55/82) in those with dermatitis and only 5/50 in those without atopic symptoms. The only difference between the new test and the RAST is that a mixture of food and inhalant allergens, rather than a single allergen, is conjugated to the paper disk and the results are expressed as positive or negative so as to identify atopic subjects for further allergologic evaluation. The sensibility and specificity of Phad-P as compared to RAST were respectively 87% and 85% with an efficiency of 86%. On the basis of these data, assuming a 20% prevalence of atopy, in the general population the predictive value of negative results of the new test would be 97% and of positive results 59% with an expected efficiency of 86% values similar to those observed in other studies and at the moment considered satisfactory for a screening test fo atopy.

Immunodeficiency, growth hormone deficiency and central nervous system involvement in a girl.

We describe a mentally retarded 12-year-old girl with ataxia in whom diagnostic evaluation for short stature revealed isolated growth hormone (GH) deficiency and multiple central nervous system (CNS) lesions. Assessment of immunologic status, performed because of the persistence of recurrent respiratory tract infections, showed associated deficiencies of IgG2-IgG4 and specific antibody response; in addition, in vitro lymphocyte response to mitogens was low, in vitro production of interleukin-2 and of IgM was absent, and natural killer activity was decreased. The possibility that association of the CNS lesions, GH deficiency and immune defects could be due to alterations of the neuro-immuno-endocrine network secondary to a disturbance of neurotransmitters induced by precocious CNS damage of a viral or ischemic nature is discussed.

[Clinical implications of sensitization to inhalants in atopic dermatitis]. / Implicazioni cliniche della sensibilizzazione ad inalanti nella dermatite atopica.

In 104 children with atopic dermatitis (AD) and RAST tests for 2 inhalant and 9 food allergen mixtures, RAST results, severity of skin involvement and presence of respiratory symptoms by history were analyzed in addition to total serum IgE values available in 66 children. Overall frequency of sensibilization was high (74%) with more positive RAST results for foods than inhalants, although of the latter the only two tested were among the more frequently positive. When the subjects positive for inhalants were considered alone, the frequency of respiratory symptoms was significantly higher in those sensitized to both inhalant mixtures tested (dermatophagoides and graminaceae) and the presence of more severe skin lesions was more common among those sensitized to graminaceae.

A comparison of secretory antibodies in breast-fed and formula-fed infants over the first six months of life.

In the present study salivary IgA, anti-Escherichia coli, anti-beta-lactoglobulin and anti-poliovirus type 1 IgA and IgM in serum and saliva were evaluated longitudinally in 13 breast-fed and 14 formula-fed infants over the first six months of life. Salivary IgA was quantified by electroimmunodiffusion; specific IgA and IgM antibodies were determined in serum and saliva by ELISA. Salivary IgA was significantly lower at age one month in breast-fed compared with formula-fed infants but in breast-fed infants salivary IgA increased with age and was significantly higher at six months than at one month. In both groups of infants, at the age of six months, salivary IgA levels were significantly lower than in adult controls. No significant differences in secretory anti-E. coli were observed between the two groups of infants. Salivary anti-poliovirus IgA and IgM antibodies increased transiently only to disappear in most babies at age six months, while anti-beta lactoglobulin IgA and IgM, present in saliva at all ages, showed a wide scatter. No important differences in specific serum IgA or IgM antibodies were observed either between the groups or at different times within the groups.

X-linked agammaglobulinemia and isolated growth hormone deficiency.

No further reports of associated X-linked hypogammaglobulinemia and isolated growth hormone deficiency have appeared in the literature since the description of the first affected family, two brothers and two maternal uncles, by Fleisher et al. in 1980. We report here a 13-year-old boy with X-linked agammaglobulinemia and isolated growth hormone deficiency, also probably inherited as an X-linked trait. The height of an older agammaglobulinemic brother who died at 6 years of age was below the third percentile.

Screening for delayed-hypersensitivity in Italian children: multicentric study by multitest skin testing.

The Multitest skin test allows the simultaneous intradermal application of seven standardized recall antigens in a reproducible manner. Response reading is based on a scoring system that distinguishes between normal and diminished delayed hypersensitivity (DH). To determine incidence and size of DH responses for each antigen in relation to age and sex in healthy Italian children, a multicentric study was performed on a representative paediatric population of 491 subjects (285 males and 296 females) aged from 4 months to 16 years. In both sexes DH reactivity as measured by score and number of positive responses increased significantly with age. The incidence of anergy was 8.8% for the whole population and decreased significantly with age in both sexes. Incidence of positive responses was highest for tetanus and diphteria toxoids, intermediate for Candida, Proteus and Streptococcus, and lowest for tuberculin and Trichophyton antigens. There was no significant difference between sexes in the incidence of positive response to each antigen.