Collagen-induced arthritis in C57BL/6 (H-2b) mice: new insights into an important disease model of rheumatoid arthritis

Collagen-induced arthritis (CIA) is a widely used model of rheumatoid arthritis (RA) and has been important for understanding autoimmunity. CIA is purportedly restricted to mice bearing the MHC class II H-2q or H-2r haplotypes. In this study, we re-examined established concepts regarding susceptibility to CIA. We found mice derived from the C57BU6 (B6) (H-2b) background can develop CIA with high incidence (60-70%), and sustained severity by using an immunization procedure modified for optimum response in DBA/1 (D1) (H-2q) mice. Clinically and histologically the B6 disease resembles that of D1 mice and is dependent on immunization with type II collagen, as well as on B and CD4+ T cells. In contrast, 129/Sv mice, which share H-2b, are resistant to CIA. We conclude that susceptibility to CIA may reflect immunization conditions and/or important contributions from non-MHC genes, revealed by different immunization protocols. A practical outcome is that CIA can be directly applied to gene knockout mice generated from B6 embryonic stem cells without need for backcross onto the D1 background. This model may lead to improved understanding of autoimmunity in CIA and RA and may provide a platform for analysis of the contribution of non-MHC genes to CIA.     

February 2003: a 53-year-old male with new onset seizures

The February COM. A 53-year-old obese man presented with new onset seizures and an MRI scan revealed a large cystic and necrotic heterogeneously enhancing left frontal mass. Craniotomy revealed a firm subdural tumor on the cortical surface that was delivered en-bloc preserving the pial planes and stripping it from the falx cerebri. The tumor consisted of multiple irregular fragments of white-tan rubbery tissue admixed with globules of bosselated, white-tan rubbery tissue and a fragment of bone. Sections of the tumor revealed mature hyaline cartilage with no atypia of the chondrocytes. There was focal mineralization and endochondral ossification. A diagnosis of intracranial mesenchymal osteochondroma was made. Osteochondroma, a benign cartilaginous neoplasm comprised of mature hyaline cartilage with focal ossification, is the most common benign bone tumor. Extraskeletal (mesenchymal) osteochondromas are known to originate from non-skeletal or non-cartilaginous tissue. Intracranial osteochondromas are uncommon, typically arising from the base of the skull. Only about 15% of intracranial osteochondromas arise supratentorially, from the dura, usually in a parafalcine frontoparietal location and some have been a component of Maffucci's syndrome and Ollier disease. Intracranial osteochondromas can occur at any age with a predilection for younger individuals. Intracranial mesenchymal osteochondromas exhibit a benign clinical course. Typically, the histomorphology resembles mature hyaline cartilage without anaplastic proliferation of chondrocytes or nuclear atypia, with a lobular arrangement of clusters of lacunae containing single chondrocytes. Transition to osteochondrosarcoma has rarely been documented.     

Expression of lysosome-associated membrane proteins in human colorectal neoplasms and inflammatory diseases

The lysosome-associated membrane proteins (LAMPs)-1 and -2 are major constituents of the lysosomal membrane. These molecules are known to be among the most glycosylated proteins of several types of cells and cancer cells, and their expression in cancer cells is marked by a distinct difference in the structures of the oligosaccharides as compared to nonmalignant cells. We analyzed by immunohistochemistry the intensity and distribution of LAMP-1 and LAMP-2 in 9 human colorectal cancer cases and in 16 control cases, including inflammatory diseases (diverticulitis, ulcerative colitis, and Crohn's disease). LAMP proteins were expressed more intensely in the epithelium of colorectal neoplasms than in normal mucosa (P < 0.05), and no significant differences were found between adenoma and cancer cells (P > 0.05) in the same tissue section. Further, in sites of inactive inflammatory diseases and nonneoplastic areas in cancer specimens, no significant increases in epithelial LAMP proteins were observed, even in the proliferative zone of the lower crypt epithelium. Northern blot analysis showed increased expression of LAMP-1 and LAMP-2A in two of three colorectal cancers examined and increased LAMP-2B in all three cancers. Our findings suggest that LAMPs are related to neoplastic progression, but there is no direct association between the expression of LAMP molecules and cell proliferation.     

Diagnostic methods for insect sting allergy

PURPOSE OF REVIEW: This review overviews advances from mid-2002 to the present in the validation and performance methods used in the diagnosis of Hymenoptera venom-induced immediate-type hypersensitivity. RECENT FINDINGS: The general diagnostic algorithm for insect sting allergy is initially discussed with an examination of the AAAAI's 2003 revised practice parameter guidelines. Changes as a result of a greater recognition of skin test negative systemic reactors include repeat analysis of all testing and acceptance of serology as a complementary diagnostic test to the skin test. Original data examining concordance of venom-specific IgE results produced by the second-generation Pharmacia CAP System with the Johns Hopkins University radioallergosorbent test are presented. Diagnostic performance of honeybee venom-specific IgE assays used in clinical laboratories in North America is discussed using data from the Diagnostic Allergy Proficiency Survey conducted by the College of American Pathologists. Validity of venom-specific IgE antibody in postmortem blood specimens is demonstrated. The utility of alternative in-vivo (provocation) and in-vitro (basophil-based) diagnostic testing methods is critiqued. SUMMARY: This overview supports the following conclusions. Improved practice parameter guidelines include serology and skin test as complementary in supporting a positive clinical history during the diagnostic process. Data are provided which support the analytical performance of commercially available venom-specific IgE antibody serology-based assays. Intentional sting challenge in-vivo provocation, in-vitro basophil flow cytometry (CD63, CD203c) based assays, and in-vitro basophil histamine and sulfidoleukotriene release assays have their utility in the study of difficult diagnostic cases, but their use will remain as supplementary, secondary diagnostic tests.     

Eighty consecutive cases of gamete intra-Fallopian transfer

Eighty patients with the main problems of unexplained infertility,oligospermia and endometriosis were treated with gamete intraFallopiantransfer (GUT). From 80 treatment cycles, 29 women conceived(36.3%). Of these, four were biochemical pregnancies and thereforethe clinical pregnancy rate (25/80) was 31.2%. There were sixsets of multiple pregnancies, a multiple pregnancy rate of 24%.Three women (12%) miscarried. The pregnancy rates in the patientswith unexplained infertility, oligospermia and endometriosiswere 33.3, 16.7 and 38.5%, respectively. The transfer of fouroocytes appears to increase the pregnancy rate without increasingthe risk of multiple pregnancy. The presence of in-vitro fertilizationof excess oocytes after GIFT did not correlate with the finaloutcome of GIFT     

Filipino beta zero thalassaemia: a high Hb A2 beta zero thalassaemia resulting from a large deletion of the 5'' beta globin gene region.

A large novel deletional beta zero thalassaemia mutation associated with unusually high levels of haemoglobin (Hb) A2 in heterozygotes is described in two unrelated subjects of Filipino background. The deletion was characterised by DNA mapping including pulsed field gel electrophoresis. Filipino beta zero thalassaemia extends for approximately 45 kb beginning approximately 1.5 kb 3' to the delta globin gene. It is the largest deletion to date which gives rise to the beta zero thalassaemia phenotype. This mutation, similar to previously described deletional beta zero thalassaemias associated with high Hb A2, removes sequences 5' to the beta globin gene promoter and emphasises the functional importance of the 5' beta globin region in eliciting the unusually high level of Hb A2. This example also suggests that it is the 3' sequences which are transposed rather than the actual deletion size which are significant in the raised fetal haemoglobin (Hb F) found with some of the thalassaemias.     

Autoantibody response to the Ro/La particle may predict outcome in neonatal lupus erythematosus.

This study was undertaken to determine the role of antibodies against both recombinant Ro (r-Ro) and La (r-La) proteins and polypeptides derived from the recombinant La protein in predicting fetal and neonatal outcome in children at risk to develop neonatal lupus erythematosus (NLE). All sera were obtained in the perinatal period and quantitative ELISA assays were used. We collected 41 maternal sera within 2 months of delivery of a child with NLE (21 with congenital heart disease block (CHB) and 20 with dermatologic NLE) and 19 sera from anti-Ro and/or anti-La antibody-positive mothers with systemic lupus erythematosus (SLE) who delivered a child without NLE. All sera were tested for anti-r-La and anti-r-Ro antibodies by ELISA, and most sera were tested for antibodies directed against La polypeptides by immunoblot. We found significantly higher anti-r-La antibody levels in the sera from mothers of children with NLE compared with sera from mothers of unaffected children (0.67 +/- 0.43 versus 0.14 +/- 0.30; P < 0.0001). There was a statistically significant difference in the mean anti-r-La levels between the sera of mothers of children with CHB compared with dermatologic NLE (0.51 +/- 0.45 versus 0.83 +/- 0.37 respectively; P = 0.0091). When we examined antibodies directed against the recombinant 52-kD Ro protein, there was a statistically significant elevation of titres in the sera of mothers of NLE children (0.77 +/- 0.35) compared with non-NLE mothers (0.29 +/- 0.39; P < 0.0001). There was no difference in the r-Ro levels between mothers of children with dermatologic NLE compared with CHB (0.82 +/- 0.37 versus 0.71 +/- 0.74; P = 0.32). When we examined polypeptides derived from the recombinant La protein, the mean number of polypeptides recognized by sera from mothers of children with NLE was significantly higher than the mean number of polypeptides recognized by sera from mothers of unaffected children (5.1 +/- 0.54 versus 2.3 +/- 0.54 respectively; P < 0.001). More importantly, when we examined the individual polypeptides, we found that only sera from mothers of children with NLE and not from mothers of unaffected children recognized a polypeptide designated DD (30% versus 0%, respectively). These studies indicate that the autoantibody response to the Ro/La particle can differentiate sera from mothers of children with NLE and sera from mothers of unaffected children. Furthermore, there was a difference in the anti-La autoantibody response between mothers of children with CHB and dermatologic NLE.(ABSTRACT TRUNCATED AT 400 WORDS)