Pentraxin 3 (PTX3) inhibits plasma cell/stromal cell cross‐talk in the bone marrow of multiple myeloma patients

Pentraxin 3 (PTX3) is a soluble pattern recognition receptor that binds with high affinity and selectivity to fibroblast growth factor‐2 (FGF2), thus inhibiting its pro‐angiogenic activity. Here we investigated the effects of PTX3 on monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) patient‐derived bone marrow (BM) plasma cells (PCs), endothelial cells (ECs), and fibroblasts (FBs), and assessed whether PTX3 can modulate the cross‐talk between PCs and those microenvironment cells. PTX3 and FGF2 expression was evaluated by ELISA. Functional studies, including cell viability, wound healing, chemotaxis, and Matrigel^® assays, were performed on MGUS and MM ECs and FBs upon the PTX3 treatment. Through western blot PTX3‐induced modulation in FGF2/FGF receptor signalling pathways was evaluated in MGUS and MM ECs and FBs through western blot. Co‐cultures between MM ECs/FBs and human PC lines were used to evaluate possible PTX3 indirect effects on MM PCs. Adhesion molecules were studied by flow cytometry. PTX3 provides a direct time‐ and dose‐dependent apoptotic effect on MM ECs and FBs, but not on either MM primary PCs or human PC lines. PTX3 inhibits migration of MM ECs and FBs in a dose‐dependent manner, and impacts in vitro and in vivo FGF2‐mediated MM angiogenesis. Co‐cultures of PCs and ECs/FBs show that PTX3 treatment indirectly impairs PC viability and adhesion. We conclude that PTX3 is an anti‐angiogenic factor in MM and behaves as a cytotoxic molecule on MM cells by inhibiting the cross‐talk between PCs and ECs/FBs. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Successful Treatment with Cyclosporine A of HCV-Driven Chronic Liver Disease Mimicking Autoimmune Hepatitis in a Patient with Common Variable Immunodeficiency

Common variable immunodeficiency (CVID) is the commonest primary immunodeficiency disease characterized by defective antibody production and various degrees of T cell numbers abnormality or impaired proliferation to mitogens. Clinical features include recurrent bacterial sinopulmonary and gastrointestinal infections. Autoimmunity is very common in CVID, occurring in approximately 25% of the patients particularly with autoimmune thrombocytopenia, hemolytic anemia, inflammatory bowel disease, and rheumatoid arthritis. Persistent antigen stimulation, secondary to a defective eradication of pathogens followed by a compensatory exaggerated chronic inflammatory response, is the primary cause leading to autoimmunity. Here we describe a girl with CVID in whom a chronic liver disease mimicking autoimmune hepatitis developed after hepatitis C virus infection. The immunosuppressive treatment with cyclosporine A proved effective in reversing liver disease.     

An analysis of the human chemokine CXC receptor 4 gene

In this article we analyze some of the structural characteristics of the coding section and the intron of the human chemokine CXC receptor 4 (a 7-transmembrane receptor) pre-mRNA. In the coding sequence the frequencies of the individual nucleotides do not depart significantly from 0.25, while in the intron the frequencies of the As and Gs are significantly lower and higher, respectively, than expected from a random distribution. Analysis of the pattern of association of nucleotides into triplets or couples shows that some triplets or couples occur with frequencies significantly higher or lower than expected when assuming a random association of nucleotides. In particular, in the intron combinations of the same nucleotide are over-represented. 7-or-more nucleotide repeats occur in both the coding section and the intron with frequencies which exceed the confidence limits for a random distribution. For the coding sequence this is possibly explained by the alternans of relatively similar hydrophobic-coding sections and relatively similar intervening intracellular and extracellular hydrophilic-coding sections. 7-or-more nucleotide repeats in reverse order and in reverse/complemented order occur in the intron, but not in the coding section, with frequencies which significantly exceed a random distribution. The numerous intronic repeats in reverse/complemented order may be of relevance for the secondary structure of the intron and might be one important element of the integrated splicing code.     

Mutation Patterns in the Chemokine CXC Receptor 4 Gene Subfamily

Six representative CXCR4 mRNAs of fish, amphibia, birds, and mammals were selected to study the pattern of conservation/mutation of the individual nt of the coding sequences. According to an arbitrary conservation index ranging from 1 to 6, the indexes of conservation were: 5.04 for the first nt of coding triplets; 5.34 for the second nt of triplets, and 3.75 for the third nt of triplets. The average conservation index of the individual triplets was 4.71. The conservation index of the seven hydrophobic transmembrane domains was 5.60, while the cumulative conservation index of the intracytoplasmic and extracellular domains was 4.63. Separate autocorrelation and power spectral analyses of the series of conservation indexes for the first nt, the second nt and the triplets demonstrated a modest “basic” positive correlation for about the first 20 lags and accordingly some power concentration at the lower frequencies (long periods). Within the triplets, the correlation was studied between the conservation indexes of nt 1 and 2, 1 and 3, and 2 and 3. Correlations of 1 with 3 and 2 with 3 were positive, but in the range of the basic local correlation, whereas the correlation between the first and second nt was significantly higher. This correlation, together with the higher conservation of the second nt as compared to the first (two patterns also found in the formyl peptide receptors), are likely to have been established by selection processes directed towards a functional conservation or a “functional repair.”     

Homogeneity of Trypanosoma cruzi I, II, and III populations and the overlap of wild and domestic transmission cycles by Triatoma brasiliensis in northeastern Brazil

The genetic variability of 24 Trypanosoma cruzi isolates from humans (11) and triatomines (13) in northeastern Brazil was analyzed by random amplified polymorphic DNA (RAPD) and compared with taxonomic groups, host, and geographical origin of the parasite. TcI (12.5 %), TcII (45.8 %), and TcIII (41.6 %) showed a similarity coefficient (SC) of 0.74 using the mean of three primers and 0.80, 0.75, and 0.66 for λgt11-F, M13-40F, and L15996 primers, respectively. The samples were clustered according to their phylogenetic origin in two polymorphic and divergent branches: one associated with TcI and the other with two subbranches corresponding to TcII and TcIII. TcI was only identified in humans and correlated with the Id homogenous group (0.80 SC). TcII from humans and Triatoma brasiliensis showed 0.86 SC and was clustered according monoclonal or polyclonal populations with similar RAPD profiles detected among the vector and/or humans in different municipalities. TcIII was isolated exclusively in sylvatic cycles from T. brasiliensis and Panstrongylus lutzi and showed low variability (0.84 SC) and high homology mainly among isolated populations at the same locality. The homology of T. cruzi among different hosts and locations suggests the distribution of principal clones circulating and reveals an overlapping between the sylvatic and domestic cycles in this area, where T. brasiliensis infected with TcII acts as link in both environments. This species is important to maintain TcII and TcIII in wild cycles and deserves particular attention due an emergent risk of these populations being introduced into the domestic cycle; moreover, its clinical and epidemiological implications remain unknown.