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Individuals with impaired cell mediated immunity exhibit increased susceptibility to infections caused by poorly pathogenic mycobacteria (non-tuberculous mycobacteria and BCG), as well as salmonella species. However, these infections may also occur in a disseminated, fatal form, sometimes with a familial distribution, in the absence of any recognised primary or secondary immunodeficiency. Genetic analysis of affected families has defined mutations in seven different genes participating in the interleukin 12 (IL12) dependent, high output interferon γ (IFNγ) pathway. The first category of defect is mutations in the IFNγR1 or R2 genes, resulting in defective expression or function of the IFNγ receptor. The second category of mutations abrogates the cell surface expression IL12Rβ1gene, resulting in the inability to respond to IL12. The third category of defect is the inability to produce IL12, due to deletion within the gene coding for the inducible chain of IL12 (IL12-p40). Patients with X-linked recessive mutations of the gene encoding the NFκB essential modulator may also develop mycobacterial infections, although they usually have a more complex phenotype and are susceptible to a broad spectrum of pathogens. Mutations of the gene encoding the signal transducing molecule STAT1, which impairs the ability to respond to IFNγ, and mutations of the gene encoding TYK2 (which is associated with a failure to respond to IL12), are both rare genetic defects predisposing to mycobacterial infections. This review summarises the clinical spectrum seen in this group of patients and indicates a strategy for the identification of putative genetic defects in the type-1 cytokine pathway.

Common Variable Immunodeficiency (CVID) comprises a heterogeneous group of primary antibody deficiencies which lead to a range of complications, including infectious, neoplastic and inflammatory disorders. This report describes monozygotic twin brothers with CVID who developed cryptogenic liver disease and subsequently hepatopulmonary syndrome (HPS). This is the second report of the association of HPS and CVID. Its occurrence in two identical twins implicates a genetic basis.

We evaluated a patient with disseminated Mycobacterium tuberculosis and Mycobacterium chelonae infection, of which he died. He also developed autoimmune (type I) diabetes and primary hypothyroidism. His serum contained a high titer of immunoglobulin G autoantibody to interferon-γ (IFN-γ) capable of blocking in vitro responses to this cytokine by peripheral blood mononuclear cells from normal donors. These results suggest that autoantibodies to IFN-γ can induce susceptibility to disseminated mycobacterial infection, which may be refractory to chemotherapy.

The auto-inflammation and phospholipase Cγ2 (PLCγ2)-associated antibody deficiency and immune dysregulation (APLAID) syndrome is a rare primary immunodeficiency caused by a gain-of-function mutation S707Y in the gene previously described in two patients from one family. The APLAID patients presented with early-onset blistering skin lesions, posterior uveitis, inflammatory bowel disease (IBD) and recurrent sinopulmonary infections caused by a humoral defect, but lacked circulating autoantibodies and had no cold-induced urticaria, contrary to the patients with the related PLAID syndrome. We describe a new APLAID patient who presented with vesiculopustular rash in the 1st weeks of life, followed by IBD, posterior uveitis, recurrent chest infections, interstitial pneumonitis, and also had sensorineural deafness and cutis laxa. Her disease has been refractory to most treatments, including IL1 blockers and a trial with ruxolitinib has been attempted. In this patient, we found a unique heterozygous missense L848P mutation in the gene, predicted to affect the PLCγ2 structure. Similarly to S707Y, the L848P mutation led to the increased basal and EGF-stimulated PLCγ2 activity . Whole blood assays showed reduced production of IFN-γ and IL-17 in response to polyclonal T-cell stimulation and reduced production of IL-10 and IL-1β after LPS stimulation. Reduced IL-1β levels and the lack of clinical response to treatment with IL-1 blockers argue against NLRP3 inflammasome hyperactivation being the main mechanism mediating the APLAID pathogenesis. Our findings indicate that L848P is novel a gain-of-function mutation that leads to PLCγ2 activation and suggest cutis laxa as a possible clinical manifestations of the APLAID syndrome.

The case of a previously healthy HIV seronegative woman with disseminated Mycobacterium tuberculosis infection and markedly reduced interferon γ production is reported here. Complete healing of her disseminated lesions was seen only after addition of subcutaneous interferon γ to her tuberculosis treatment.

It is questionable as to whether a low serum concentration of one of the IgG subclasses identifies a disease state. A low IgG1 concentration is found in primary or secondary immunodeficiency states but does not occur in isolation. Low IgG2 concentration is associated with an increased risk of bacterial infections but only in some individuals and not in others. Isolated IgG3 and IgG4 deficiency have not been convincingly demonstrated. Therefore, the isolated finding of low concentrations of one or more IgG subclass does not identify individuals at risk. In contrast, the finding of low serum concentrations of antibodies to specific bacterial antigens (Haemophilus influenzae type B, pneumococcus, tetanus and diphtheria) does identify individuals at risk and these measurements should be used in preference to IgG subclass measurement.

Patients with inherited deficiency of the interleukin (IL)-12/IL-23-interferon (IFN)-γ axis show increased susceptibility to invasive disease caused by the intramacrophage pathogens salmonellae and mycobacteria. We analyzed data on 154 patients with such deficiency. Significantly more patients with IL-12/IL-23-component deficiency had a history of salmonella disease than did those with IFN-γ-component deficiency. Salmonella disease was typically severe, extraintestinal, and caused by nontyphoidal serovars. These findings strongly suggest that IL-12/IL-23 is a key cytokine for immunity against salmonella in humans and that IL-12/IL-23 mediates this protective effect partly through IFN-γ-independent pathways. Investigation of the IL-12/IL-23-IFN-γ axis should be considered in patients with invasive salmonella disease.

Interferon γ receptor 1 (IFNγ R1) deficiency is a primary immunodeficiency with allelic dominant and recessive mutations characterised clinically by severe infections with mycobacteria. We aimed to compare the clinical features of recessive and dominant IFNγR1 deficiencies. We obtained data from a large cohort of patients worldwide. We assessed these people by medical histories, records, and genetic and immunological studies. Data were abstracted onto a standard form. We identified 22 patients with recessive complete IFNγR1 deficiency and 38 with dominant partial deficiency. BCG and environmental mycobacteria were the most frequent pathogens. In recessive patients, 17 (77%) had environmental mycobacterial disease and all nine BCG-vaccinated patients had BCG disease. In dominant patients, 30 (79%) had environmental mycobacterial disease and 11 (73%) of 15 BCG-vaccinated patients had BCG disease. Compared with dominant patients, those with recessive deficiency were younger at onset of first environmental mycobacterial disease (mean 3·1 years [SD 2·5] vs 13·4 years [14·3], p=0·001), had more mycobacterial disease episodes (19 vs 8 per 100 person-years of observation, p=0·0001), had more severe mycobacterial disease (mean number of organs infected by Mycobacterium avium complex 4·1 [SD 0·8] vs 2·0 [1·1], p=0·004), had shorter mean disease-free intervals (1·6 years [SD 1·4] vs 7·2 years [7·6], p<0·0001), and lower Kaplan-Meier survival probability (p<0·0001). M avium complex osteomyelitis was more frequent in dominant than in recessive patients (22/28 [79%] vs 1/8 [13%], p=0·002), and this disorder without other organ involvement arose only in dominant patients (9/28 [32%]). Disease caused by rapidly growing mycobacteria was present in more recessive than dominant patients (7/22 [32%] vs 1/38 [3%], p=0·002). Recessive complete and dominant partial IFNγR1 deficiencies have related clinical phenotypes, but are distinguishable by age at onset, dissemination, and clinical course of mycobacterial diseases. A strong correlation exists between IFNGR genotype, cellular responsiveness to interferon γ, and clinical disease features.

OBJECTIVE--To assess the relationship between plasma levels of the cytokine interleukin-1 beta (IL-1 beta) and the progression of rheumatoid arthritis (RA). METHODS--Two subgroups of patients, one with persistently raised ESR (>/= 50 mm/hour, n = 16, group A) and one with persistently low ESR (