Immunology of Diseases Associated with Malassezia Species

Malassezia species are members of the human cutaneous commensal flora, in addition to causing a wide range of cutaneous and systemic diseases in suitably predisposed individuals. Studies examining cellular and humoral immune responses specific to Malassezia species in patients with Malassezia-associated diseases and healthy controls have generally been unable to define significant differences in their immune response. The use of varied antigenic preparations and strains from different Malassezia classifications may partly be responsible for this, although these problems can now be overcome by using techniques based on recent work defining some important antigens and also a new taxonomy for the genus. The finding that the genus Malassezia is immunomodulatory is important in understanding its ability to cause disease. Stimulation of the reticuloendothelial system and activation of the complement cascade contrasts with its ability to suppress cytokine release and downregulate phagocytic uptake and killing. The lipid-rich layer around the yeast appears to be pivotal in this alteration of phenotype. Defining the nonspecific immune response to Malassezia species and the way in which the organisms modulate it may well be the key to understanding how Malassezia species can exist as both commensals and pathogens.     

Genetics of rheumatoid arthritis

The haplotype sharing distribution in affected sib pairs are used to demonstrate the linkage of a susceptibility gene for rheumatoid arthritis (RA) to the HLA region. Family and population studies suggest heterogeneity in the etiology of RA.     

Intracellular mechanisms governing the acute phase of β-endorphin secretion from the corticotrope in vitro

It is not certain which protein kinase (A, C or both) is involved in the acute phase of β-endorphin (β-EP) release stimulated in the corticotrope by vasopressin (VP) and corticotropin-releasing factor (CRF). We have employed an isolated ovine anterior pituitary cell superfusion system to determine the dynamic effects of forskolin, a protein kinase A (PKA) stimulator, and phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator. Both secretagogues stimulated β-EP release within 5 min and therefore both PKA and PKC are potential mediators of the acute phase of hormonal stimulation of the corticotrope. Pretreatment with PMA specifically desensitized the pituitary cell columns to subsequent PMA exposure while not significantly altering sensitivity to forskolin or 50 mM KCl.     

Macrophage migration inhibitory factor (MIF) gene polymorphism is associated with susceptibility to but not severity of inflammatory polyarthritis

The aim of the study was to investigate whether polymorphisms of macrophage migration inhibitory factor (MIF) determine susceptibility to or severity of inflammatory polyarthritis (IP). Genotypes for a single-nucleotide polymorphism (MIF-173*G/C) and a tetranucleotide (CATT)(n) repeat mapping to the promoter region of the MIF gene were compared between UK Caucasian IP cases (n=438) and controls (n=343). Both polymorphisms were also investigated for association with features of disease activity and severity at baseline and by 5 years. The MIF-173*C allele (OR 1.7, 95% CI 1.3-2.4, P=1.8 x 10(-4)) and the CATT(7) allele (OR 1.5, 95% CI 1.0-2.1, P=0.02) were found to be associated with increased susceptibility to IP. Furthermore, presence of the haplotype containing both associated polymorphisms was associated with a three-fold increase risk of developing IP. No association with disease severity or activity either at baseline or by 5 years was detected for either of the promoter polymorphisms studied. In conclusion, MIF is a susceptibility gene for the development of IP. The same alleles previously reported to be associated with susceptibility to juvenile idiopathic arthritis account for the increased risk. The promoter polymorphisms of MIF, investigated in this study, do not influence the severity of disease outcome by 5 years.     

An evaluation of three methods of typing organisms of the genus Proteus

An assessment of three simple methods of typing Proteus strains is described. The methods chosen were biochemical typing, bacteriocine typing, and typing by means of the Dienes phenomenon. Dienes typing was deemed to be superior to biochemical typing and bacteriocine typing.A brief discussion on the relationship between the Dienes phenomenon and bacteriocine production is appended.     

Polysaccharides of the Genus Bacillus Cross-Reactive with the Capsular Polysaccharides of Diplococcus pneumoniae Type III, Haemophilus influenzae Type b, and Neisseria meningitidis Group A

We studied 174 strains of the genus Bacillus for cross-reacting antigens to the capsular polysaccharides of groups A and C meningococcus, types I and III pneumococcus, and Haemophilus influenzae type b. Cross-reactions were detected by immunodiffusion in agarose gel by using type-specific antisera and confirmed by absorption and inhibition experiments. Of 20 Bacillus pumilis strains, six had an antigen cross-reacting with group A meningococcal polysaccharide. Other cross-reactions included one strain of B. pumilis with H. influenzae type b, one of B. cereus var. mycoides with pneumococcus type III, and one of B. alvei with both type b and SIII polysaccharides. These cross-reacting antigens are polysaccharides of vegetative cells and may be extracellular in location. Because these bacilli have antigens cross-reacting with the virulence factors of pyogenic bacteria, they may, as normal flora, be an antigenic stimulus for "natural" serum anti-capsular antibodies to the type b Haemophilus and group A meningococcus polysaccharides.     

Spectrum of CLN6 mutations in variant late infantile neuronal ceroid lipofuscinosis

The neuronal ceroid lipofuscinoses (NCLs) are a group of autosomal recessive neurodegenerative diseases of childhood. CLN6, the gene mutated in variant late infantile NCL (vLINCL), was recently cloned. We report the identification of eight further mutations in CLN6 making a total of 18 reported mutations. These mutations include missense, nonsense, small deletions or insertions, and two splice-site mutations. Ten mutations affect single amino acids, all of which are conserved across vertebrate species. Minor differences in the pattern of disease symptom evolution can be identified. One patient with a more protracted disease progression was a compound heterozygote for a missense mutation and an unidentified mutation. Fifteen CLN6 mutations occur in one or two families only, and families from the same country do not all share the same mutation. Unlike NCLs caused by mutations in CLN1, CLN3, CLN5, and CLN8, there is no major founder mutation in CLN6. However, one mutation (E72X) is significantly more common in patients from Costa Rica than two other mutations present in that same population. In addition, a 1-bp insertion (c.316insC) is associated with families from Pakistan and I154del may be common in Portugal. A group of Roma Gypsy families from the Czech Republic share two disease-associated haplotypes, one of which is also present in a Pakistani family, consistent with the proposed migration of the Roma from the Indian subcontinent 1,000 years ago. All mutations are recorded in the NCL Mutation Database together with their country of origin for use in the development of rapid screening assays to confirm diagnosis and to facilitate carrier testing appropriate to a population.     

Cross-regulatory role of interferon-gamma (IFN-gamma), IL-4 and IL-10 in schistosome egg granuloma formation: in vivo regulation of Th activity and inflammation.

This study examined the relationship of IL-4, IL-10 and IFN-gamma with regard to the local granuloma (GR) and draining lymph node (LN) response to Schistosoma mansoni eggs. Synchronized GR were induced in naive and schistosome-infected mice at the vigorous (8 weeks) and late chronic (20 weeks) stages. In LN cultures, IL-10 and IFN production peaked on day 4 and was greatest for 8 week-infected mice. All GR cultures contained IFN, but compared with naive mice IL-10 production was accelerated at 8 weeks and abrogated at 20 weeks, consistent with expansion and abatement of Th2 activity. Cytokine neutralization was performed in egg-challenged, naive mice that were adoptively sensitized with lymphoid cells from 8 week-infected donors. GR size, GR macrophage tumour necrosis factor (TNF) production and egg antigen-elicited IL-2, IL-4, IL-5, IL-10 and IFN were examined on day 4 of GR formation. Anti-IFN augmented GR area by 40%, increased local IL-4 and IL-10, but decreased IFN and TNF production. In corresponding LN cultures, IFN decreased by about 50%, while IL-2, IL-4, IL-10 and IL-5 increased by nearly two-, four-, five- and six-fold, respectively. Anti-IL-10 did not affect GR size or GR cytokines, but abrogated GR area by 40%, along with a reduction in local IL-4 and TNF production. In LN, IL-4 depletion reduced IL-4 and IL-5 by 60-70% and increased IFN levels. These results support the notion of a cross-regulatory network in which IFN inhibits Th2 and IL-10 inhibits Th1 cells. IL-4 fosters Th2 cells differentiation in LN, but also performs a critical recruitment function in the eosinophil-rich schistosome egg-induced GR, whereas IFN contributes to enhanced GR macrophage function.