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Summary Sarcoidosis is a systemic disorder characterized by the formation of non-caseating granulomas in variable organs. Toll-like receptor (TLR)-9 is important in the innate immune response against both Mycobacterium tuberculosis and Propionibacterium acnes, candidate causative agents in sarcoidosis. The aim of our study was to investigate possible genetic and functional differences in TLR-9 between patients and controls. TLR-9 single nucleotide polymorphisms were genotyped in 533 patients and divided into a study cohort and validation cohort and 185 healthy controls. Furthermore, part of the promotor as well as the entire coding region of the TLR-9 gene were sequenced in 20 patients in order to detect new mutations. No genetic differences were found between patients and controls. In order to test TLR-9 function, peripheral blood mononuclear cells (PBMCs) of 12 healthy controls and 12 sarcoidosis patients were stimulated with a TLR-9 agonist and the induction of interleukin (IL)-6, interferon (IFN)-γ and IL-23 was measured. Sarcoidosis patients produce significantly less IFN-γ upon stimulation with different stimuli. Regarding IL-23 production, a significant difference between patients and controls was found only after stimulation with the TLR-9 agonist. In conclusion, we did not find genetic differences in the TLR-9 gene between sarcoidosis patients and controls. Sarcoidosis patients produce less IFN-γ regardless of the stimulating agent, probably reflecting the anergic state often seen in their peripheral blood T lymphocytes. The differences in TLR-9-induced IL-23 production could indicate that functional defects in the TLR-9 pathway of sarcoidosis patients play a role in disease susceptibility or evolution.

Newborn babies possess a functional but immature immune system as a defense against a world teeming with microorganisms. Breast milk contains a number of biological, active compounds that support the infant's immune system. These include secretory immunoglobulin A (IgA), which confers specific protection against enteric pathogens, as well as numerous other immunological, active ingredients. A number of these ingredients can be used as supplements for infant formulas based on cow's milk. Here, the strength of evidence regarding the immune-stimulating effects of selected minerals, vitamins, fatty acids, pre- and probiotics, and nucleotides is reviewed. An assessment of how these ingredients are used in infant-formula products currently available on the market is also presented.

Haemophilus influenzae type b (Hib) conjugate vaccines are extremely effective in protecting infants and children from invasive Hib infections; however, vaccine failures do occur. The anti-Hib antibody production was studied both quantitatively and qualitatively in 12 patients who experienced Hib failure, all of whom had normal serum immunoglobulin concentrations and all of whom were without clinical risk factors for invasive Hib disease. Both anti-Hib antibody concentration and immunoglobulin-G2 anti-Hib antibody avidity were significantly lower in patients who experienced Hib failure, at onset of disease and after reconvalescence, when compared with controls. This finding suggests that the patients who developed invasive Hib disease--despite having received 3-4 Hib conjugate vaccinations--were inadequately primed by these vaccinations.

Objectives. The hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) was found recently to be caused by a deficiency of mevalonate kinase (MK). The aim of this study was to examine whether a relationship exists between the clinical expression of HIDS and the extent of MK deficiency. Methods. The medical records of children diagnosed with HIDS were reviewed for clinical features and serum immunoglobulin values. The mevalonic acid excretion in urine and MK enzyme activity in patients' cells were measured and the cDNA of the MVK gene was sequenced. Results. Fifteen patients with recurrent fever and raised serum immunoglobulin (Ig) D were included. Their clinical features varied. Eleven patients had a deficiency of MK, caused by mutations in the MVK gene. One mutation (V377I) was common to all 11 patients. Nine patients were compound heterozygotes for V377I and various other MVK mutations. There was no apparent relationship between the observed mutations and the clinical features. Surprisingly, four boys had normal MK activity and no MVK mutations. Conclusions. Most HIDS patients have mutations in the MVK gene. The clinical variability observed cannot be explained by genotypic differences. Periodic fever and elevated IgD can result from other, still unknown, causes. Hence, testing for MK deficiency is necessary in patients with unexplained periodic fever.

A prospective study of antibody production by adults infected with human immunodeficiency virus (HIV) after vaccination with tetanus toxoid-conjugated Haemophilus influenzae type b (Hib) vaccine was conducted. Concentrations of antibodies to the two immunogenic components of the vaccine (i.e., polyribosylribitolphosphate [PRP] and tetanus toxin) were determined. Individuals were divided into three groups according to the CD4+ T lymphocyte count: group 1,or =100 x 10(6)/L; group 2, 101-300 x 10(6)/L; and group 3,300 x 10(6)/L. After vaccination, concentrations of IgM and IgG antibodies to PRP were significantly lower in group 1 than in the other patient groups and controls. A CD4+ T lymphocyte count of100 x 10(6)/L and an impaired proliferative response of lymphocytes to monoclonal antibody to CD3 were independently associated with a less than threefold increase in concentrations of IgG antibody to PRP. Analysis of IgG subclasses demonstrated that the production of IgG1 antibodies was predominantly affected. Postvaccination concentrations of antibody to tetanus toxin were significantly lower in group 1 than in group 3 and controls. Both prevaccination and postvaccination concentrations of antibody to tetanus toxin were not correlated with the magnitude of the response of antibody to PRP. We conclude that HIV-infected individuals with CD4+ T Iymphocyte counts of100 x 10(6)/L demonstrate an impaired antibody response after vaccination with conjugated Hib vaccine.

SUMMARY To investigate the possible role of Cryptococcus neoformans var. neoformans in HIV disease progression, and to identify the responsible cryptococcal components, an in vitro cell culture model was set up to study the C. neoformans-induced enhancement of HIV replication in HIV-1-infected PBMC. Similar to whole C. neoformans, cell-wall membrane fraction and mannoproteins induced proliferation of PBMC and enhancement of lymphotropic HIV replication in HIV-infected PBMC, while galactoxylomannan did not. MoAbs capable of interfering with MHC class II-mediated antigen presentation prevented the induction of cell proliferation by whole C. neoformans or cryptococcal mannoproteins. MoAb binding to adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1) also inhibited C. neoformans-induced cell proliferation. In addition, anti-MHC class II MoAb inhibited the enhancement of HIV replication by C. neoformans. The results suggest that: (i) C. neoformans may accelerate HIV disease progression by stimulation of HIV replication through MHC class II-mediated antigen presentation; and (ii) cryptococcal mannoprotein may be one of the responsible components. The ability to enhance HIV replication in PBMC in vitro is not unique for C. neoformans. However, this is the first report to study in detail a yeast-induced enhancement of HIV replication in PBMC.

Fc gamma RIIa (CD32) is the sole IgG Fc receptor capable of interaction with human IgG2, the main IgG subclass of bacterial capsular polysaccharides. The two genetically determined allotypes of human Fc gamma RIIa, Fc gamma RIIa-R131 and IIa-H131 alleles, have functionally different reactivities with human IgG2. The capacity of polymorphonuclear leukocytes (PMNL) homozygous for Fc gamma RIIa-H/H131 for IgG2 opsonized bacteria is significantly higher than phagocytosis by PMNL homozygous for Fc gamma RIIa-R/R131, independent of the Fc gamma RIIb-NA1/NA2 (CD16) allelic polymorphism. To test the clinical significance of these Fc gamma R polymorphisms, Fc gamma RIIa and Fc gamma RIIIb phenotypes of 48 children with recurrent bacterial respiratory tract infections were determined. Fc gamma RIIa-H/H131 was less than half that observed in 123 healthy adults (P = .01). IgG2 responses were low in 25 of 48 patients after immunization with pneumococcal vaccine. These results suggest that Fc gamma RIIa polymorphism may contribute to increased susceptibility to infections with encapsulated bacteria in a childhood population with low IgG2 anti-carbohydrate antibodies.

Synthetically prepared ribosylribitol phosphate dimer and trimer analogous to fragments of the capsular polysaccharide of Haemophilus influenzae type b, containing either an amino- or a (masked) thiol-functionalized spacer, were conjugated to protein by two different methods. The thiol-containing carbohydrates were conjugated to tetanus toxoid or H. influenzae outer membrane protein using N-succinimidyl 3-(2-pyridyldithio)propionate. Glutaric dialdehyde was used to conjugate the amino-containing carbohydrates with tetanus toxoid. All conjugates were able to bind antibodies raised against the native bacterial polysaccharide, as determined by competition ELISA. The glutaric dialdehyde conjugate prepared from ribosylribitol phosphate trimer and tetanus toxoid induced a strong polysaccharide-specific antibody response in mice and rabbits.