Transcriptome analysis of ankylosing spondylitis patients before and after TNF-α inhibitor therapy reveals the pathways affected.

Tumor necrosis factor-α (TNF-α) inhibitors are highly effective in suppressing inflammation in ankylosing spondylitis (AS) patients, and operate by suppression of TFN-α and downstream immunological pathways. To determine the mechanisms of action of TNF-α inhibitors in AS patients, we used transcriptomic and bioinformatic approaches on peripheral blood mononuclear cells from AS patients pre and post treatment. We found 656 differentially expressed genes, including the genome-wide significant AS-associated genes, IL6R, NOTCH1, IL10, CXCR2 and TNFRSF1A. A distinctive gene expression profile was found between male and female patients, mainly because of sex chromosome-linked genes and interleukin 17 receptor C, potentially accounting for the differences in clinical manifestation and treatment response between the genders. In addition to immune and inflammation regulatory pathways, like intestinal immune network for IgA production, cytokine-cytokine receptor interaction, Ras signaling pathway, allograft rejection and hematopoietic cell lineage, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analyses revealed that infection-associated pathways (influenza A and toxoplasmosis) and metabolism-associated pathways were involved in response to TNF-α inhibitor treatment, providing insight into the mechanism of TNF-α inhibitors.

Local Expansion of Donation After Circulatory Death Kidney Transplant Activity Improves Waitlisted Outcomes and Addresses Inequities of Access to Transplantation.

In the United Kingdom, donation after circulatory death (DCD) kidney transplant activity has increased rapidly, but marked regional variation persists. We report how increased DCD kidney transplant activity influenced waitlisted outcomes for a single center. Between 2002-2003 and 2011-2012, 430 (54%) DCD and 361 (46%) donation after brain death (DBD) kidney-only transplants were performed at the Cambridge Transplant Centre, with a higher proportion of DCD donors fulfilling expanded criteria status (41% DCD vs. 32% DBD; p = 0.01). Compared with U.K. outcomes, for which the proportion of DCD:DBD kidney transplants performed is lower (25%; p < 0.0001), listed patients at our center waited less time for transplantation (645 vs. 1045 days; p < 0.0001), and our center had higher transplantation rates and lower numbers of waiting list deaths. This was most apparent for older patients (aged >65 years; waiting time 730 vs. 1357 days nationally; p < 0.001), who received predominantly DCD kidneys from older donors (mean donor age 64 years), whereas younger recipients received equal proportions of living donor, DBD and DCD kidney transplants. Death-censored kidney graft survival was nevertheless comparable for younger and older recipients, although transplantation conferred a survival benefit from listing for only younger recipients. Local expansion in DCD kidney transplant activity improves survival outcomes for younger patients and addresses inequity of access to transplantation for older recipients.

The genetic associations of acute anterior uveitis and their overlap with the genetics of ankylosing spondylitis.

Acute anterior uveitis (AAU) involves inflammation of the iris and ciliary body of the eye. It occurs both in isolation and as a complication of ankylosing spondylitis (AS). It is strongly associated with HLA-B*27, but previous studies have suggested that further genetic factors may confer additional risk. We sought to investigate this using the Illumina Exomechip microarray, to compare 1504 cases with AS and AAU, 1805 with AS but no AAU and 21 133 healthy controls. We also used a heterogeneity test to test the differences in effect size between AS with AAU and AS without AAU. In the analysis comparing AS+AAU+ cases versus controls, HLA-B*27 and HLA-A*02:01 were significantly associated with the presence of AAU (P<10(-300) and P=6 × 10(-8), respectively). Secondary independent association with PSORS1C3 (P=4.7 × 10(-5)) and TAP2 (P=1.1 × 10(-5)) were observed in the major histocompatibility complex. There was a new suggestive association with a low-frequency variant at zinc-finger protein 154 in the AS without AAU versus control analysis (zinc-finger protein 154 (ZNF154), P=2.2 × 10(-6)). Heterogeneity testing showed that rs30187 in ERAP1 has a larger effect on AAU compared with that in AS alone. These findings also suggest that variants in ERAP1 have a differential impact on the risk of AAU when compared with AS, and hence the genetic risk for AAU differs from AS.

Disease-associated polymorphisms in ERAP1 do not alter endoplasmic reticulum stress in patients with ankylosing spondylitis.

The mechanism by which human leukocyte antigen B27 (HLA-B27) contributes to ankylosing spondylitis (AS) remains unclear. Genetic studies demonstrate that association with and interaction between polymorphisms of endoplasmic reticulum aminopeptidase 1 (ERAP1) and HLA-B27 influence the risk of AS. It has been hypothesised that ERAP1-mediated HLA-B27 misfolding increases endoplasmic reticulum (ER) stress, driving an interleukin (IL) 23-dependent, pro-inflammatory immune response. We tested the hypothesis that AS-risk ERAP1 variants increase ER-stress and concomitant pro-inflammatory cytokine production in HLA-B27(+) but not HLA-B27(-) AS patients or controls. Forty-nine AS cases and 22 healthy controls were grouped according to HLA-B27 status and AS-associated ERAP1 rs30187 genotypes: HLA-B27(+)ERAP1(risk), HLA-B27(+)ERAP1(protective), HLA-B27(-)ERAP1(risk) and HLA-B27(-)ERAP1(protective). Expression levels of ER-stress markers GRP78 (8 kDa glucose-regulated protein), CHOP (C/EBP-homologous protein) and inflammatory cytokines were determined in peripheral blood mononuclear cell and ileal biopsies. We found no differences in ER-stress gene expression between HLA-B27(+) and HLA-B27(-) cases or healthy controls, or between cases or controls stratified by carriage of ERAP1 risk or protective alleles in the presence or absence of HLA-B27. No differences were observed between expression of IL17A or TNF (tumour necrosis factor) in HLA-B27(+)ERAP1(risk), HLA-B27(+)ERAP1(protective) and HLA-B27(-)ERAP1(protective) cases. These data demonstrate that aberrant ERAP1 activity and HLA-B27 carriage does not alter ER-stress levels in AS, suggesting that ERAP1 and HLA-B27 may influence disease susceptibility through other mechanisms.

The UK Pancreas Allocation Scheme for Whole Organ and Islet Transplantation.

In order to develop a national allocation scheme for donor pancreases, factors affecting waiting time and transplant outcomes in the United States (US) and United Kingdom (UK) were analyzed and compared. Blood group, sensitization, dialysis requirement, and whether the patient was waiting for a kidney and pancreas or pancreas alone affected waiting time in both countries; ethnicity and body mass index (BMI) also affected waiting time in the US. Ninety-day pancreas survival was similar in the UK and US, and was poorer for patients receiving a pancreas alone, with older donors, higher BMI and longer duration of ischemia in both countries. Factors affecting outcome, together with published data on factors affecting islet transplantation, informed the development of a points based allocation scheme for deceased donor pancreases in the UK providing equitable access for both whole organ and islet recipients through a single waiting list. Analysis of the allocation scheme 3 years after its introduction in December 2010 showed that the results were broadly as simulated, with a significant reduction in the number of long waiting patients and an increase in the number of islet transplants. There remains a surplus of highly sensitized patients in the waiting list, which the scheme should address in time.

Successful transplantation of kidneys from elderly circulatory death donors by using microscopic and macroscopic characteristics to guide single or dual implantation.

Most kidneys from potential elderly circulatory death (DCD) donors are declined. We report single center outcomes for kidneys transplanted from DCD donors over 70 years old, using preimplantation biopsy Remuzzi grading to inform implantation as single or dual transplants. Between 2009 and 2012, 43 single transplants and 12 dual transplants were performed from elderly DCD donors. Remuzzi scores were higher for dual than single implants (4.4 vs. 3.4, p < 0.001), indicating more severe baseline injury. Donor and recipient characteristics for both groups were otherwise similar. Early graft loss from renal vein thrombosis occurred in two singly implanted kidneys, and in one dual-implanted kidney; its pair continued to function satisfactorily. Death-censored graft survival at 3 years was comparable for the two groups (single 94%; dual 100%), as was 1 year eGFR. Delayed graft function occurred less frequently in the dual-implant group (25% vs. 65%, p = 0.010). Using this approach, we performed proportionally more kidney transplants from elderly DCD donors (23.4%) than the rest of the United Kingdom (7.3%, p < 0.001), with graft outcomes comparable to those achieved nationally for all deceased-donor kidney transplants. Preimplantation biopsy analysis is associated with acceptable transplant outcomes for elderly DCD kidneys and may increase transplant numbers from an underutilized donor pool.

COL1A1 C-propeptide cleavage site mutation causes high bone mass, bone fragility and jaw lesions: a new cause of gnathodiaphyseal dysplasia?

Gnathodiaphyseal dysplasia (GDD) is a rare autosomal dominant condition characterized by bone fragility, irregular bone mineral density (BMD) and fibro-osseous lesions in the skull and jaw. Mutations in Anoctamin-5 (ANO5) have been identified in some cases. We aimed to identify the causative mutation in a family with features of GDD but no mutation in ANO5, using whole exome capture and massive parallel sequencing (WES). WES of two affected individuals (a mother and son) and the mother's unaffected parents identified a mutation in the C-propeptide cleavage site of COL1A1. Similar mutations have been reported in individuals with osteogenesis imperfecta (OI) and paradoxically increased BMD. C-propeptide cleavage site mutations in COL1A1 may not only cause 'high bone mass OI', but also the clinical features of GDD, specifically irregular sclerotic BMD and fibro-osseous lesions in the skull and jaw. GDD patients negative for ANO5 mutations should be assessed for mutations in type I collagen C-propeptide cleavage sites.

Utility of temporal artery biopsy samples for genome-wide analysis of giant cell arteritis.

Giant Cell Arteritis (GCA) is the most common vasculitis affecting the elderly. Archived formalin-fixed paraffin-embedded (FFPE) temporal artery biopsy (TAB) specimens potentially represent a valuable resource for large-scale genetic analysis of this disease. FFPE TAB samples were obtained from 12 patients with GCA. Extracted TAB DNA was assessed by real time PCR before restoration using the Illumina HD FFPE Restore Kit. Paired FFPE-blood samples were genotyped on the Illumina OmniExpress FFPE microarray. The FFPE samples that passed stringent quality control measures had a mean genotyping success of >97%. When compared with their matching peripheral blood DNA, the mean discordant heterozygote and homozygote single nucleotide polymorphisms calls were 0.0028 and 0.0003, respectively, which is within the accepted tolerance of reproducibility. This work demonstrates that it is possible to successfully obtain high-quality microarray-based genotypes FFPE TAB samples and that this data is similar to that obtained from peripheral blood.

Risedronate in adults with osteogenesis imperfecta type I: increased bone mineral density and decreased bone turnover, but high fracture rate persists.

UNLABELLED: Bisphosphonates can increase bone mineral density (BMD) in children with osteogenesis imperfecta (OI). In this study of adults with OI type I, risedronate increased BMD at lumbar spine (but not total hip) and decreased bone turnover. However, the fracture rate in these patients remained high. INTRODUCTION: Intravenous bisphosphonates given to children with OI can increase BMD and reduce fracture incidence. Oral and/or intravenous bisphosphonates may have similar effects in adults with OI. We completed an observational study of the effect of risedronate in adults with OI type I. METHODS: Thirty-two adults (mean age, 39 years) with OI type I were treated with risedronate (total dose, 35 mg weekly) for 24 months. Primary outcome measures were BMD changes at lumbar spine (LS) and total hip (TH). Secondary outcome measures were fracture incidence, bone pain, and change in bone turnover markers (serum procollagen type I aminopropeptide (P1NP) and bone ALP). A meta-analysis of published studies of oral bisphosphonates in adults and children with OI was performed. RESULTS: Twenty-seven participants (ten males and seventeen females) completed the study. BMD increased at LS by 3.9% (0.815 vs. 0.846 g/cm(2), p = 0.007; mean Z-score, -1.93 vs. -1.58, p = 0.002), with no significant change at TH. P1NP fell by 37% (p = 0.00041), with no significant change in bone ALP (p = 0.15). Bone pain did not change significantly (p = 0.6). Fracture incidence remained high, with 25 clinical fractures and 10 major fractures in fourteen participants (0.18 major fractures per person per year), with historical data of 0.12 fractures per person per year. The meta-analysis did not demonstrate a significant difference in fracture incidence in patients with OI treated with oral bisphosphonates. CONCLUSIONS: Risedronate in adults with OI type I results in modest but significant increases in BMD at LS, and decreased bone turnover. However, this may be insufficient to make a clinically significant difference to fracture incidence.

Characterization of an Epstein-Barr virus receptor on human epithelial cells.

Epstein-Barr virus (EBV) adsorption to human B lymphocytes is mediated by the viral envelope glycoprotein, gp350/220, which binds to the cell surface protein, CD21, also known as the CR2 complement receptor. Human epithelial cells also express an EBV receptor. A candidate surface molecule of 195 kD has previously been identified on an epithelial cell line and explanted epithelial tissue by reactivity with the CD21 specific monoclonal antibody (mAb), HB-5a. In experiments to further characterize the epithelial cell EBV receptor, we have found that two human epithelial cell lines, RHEK-1 and HeLa, specifically bind intact EB virions. A 145-kD protein, similar in size to B lymphocyte CD21, was specifically precipitated from surface iodinated RHEK-1 cells using the HB-5a mAb, or using purified soluble gp350/220 coupled to agarose beads. The previously identified 195-kD protein did not bind to gp350/220 or react with two other anti-CD21 mAbs. CD21 homologous RNA, similar in size to the B lymphocyte CD21 mRNA, was detected in both RHEK-1 and HeLa cells. The nucleotide sequence of the epithelial cell cDNA was identical to B lymphocyte CD21. The longest clone differs from previously reported CD21 cDNAs in having additional 5' untranslated sequence. Polymerase chain reaction amplification of RHEK-1- or B lymphoblastoid-derived cDNA verified that most CD21 transcripts are initiated at least 30-50 nucleotides upstream of the previously reported mRNA cap site. These experiments demonstrate that human epithelial cells can express CD21, and that CD21 is likely to mediate EBV adsorption to epithelial cells.

Suspected venous air embolism in a horse.

A horse which had had a caecal impaction for 10 days was treated by means of an ileocolostomy [corrected] but failed to respond satisfactorily. Before a second laparotomy was performed it was observed to have dislodged the extension set from a jugular catheter and air was heard being sucked into the vein. It became very agitated but was anaesthetised again and the impaction was removed through an incision in the apex of the colon [corrected] After recovering from the anaesthesia it developed severe signs of pruritus which subsided only after 12 hours. These signs were considered most likely to have resulted from a venous air embolism.

Did exclusive breast-feeding and early discharge lead to excessive bilirubin levels in newborns in Antigua and Barbuda?

Hyperbilirubinaemia is a common neonatal problem worldwide and is the leading cause of admission to the Special Care Nursery in Antigua and Barbuda. In 1990, the Innocenti Declaration in support of breast-feeding led to the adoption of the Baby-Friendly Hospital Initiative in many countries of the Caribbean, including Antigua and Barbuda. Comparing 1989 to the years 1992 to 1994, the Special Care Nursery at Holberton Hospital experienced a 40% increase in newborns admitted with hyperbilirubinaemia (peak total bilirubin > 12 mg/dl or 205 mumol/l). A retrospective review of Special Care Nursery and Maternity Ward records was undertaken to determine the incidence and aetiology of hyperbilirubinaemia from 1992 to 1994. There were 3721 infants born in Antigua and Barbuda in those years, 98% of Afro-Caribbean or mixed ancestry. The overall incidence of peak total bilirubin over 12 mg/dl (205 mumol/l) was 12.5% (466/3721), not inconsistent with the reported incidence of 8 to 20% in other countries. However, the incidence of higher levels of hyperbilirubinaemia in Antigua and Barbuda exceeded those reported for other countries. In Antigua and Barbuda, total bilirubin of 15 mg/dl (255 mumol/l) or higher was found in 263 of 3721 infants (7.1%) compared to 5.9% in India and 2% of breast-fed infants in the United States of America (USA). Total bilirubin of 20 mg/dl (340 mumol/l) or higher was seen in 91 of 3721 infants (2.5%) exceeding reported prevalence in the USA for both African-American and Caucasian infants (1%) and equal to the reported prevalence in Asian infants (2%). The possible aetiologies of hyperbilirubinaemia in neonates with total bilirubin 18 mg/dl (306 mumol/l) or higher in our patients were investigated. Medical records of 134 of 156 (86%) infants having this level of hyperbilirubinaemia were available for review. The possible reason for hyperbilirubinaemia was ABO incompatibility in 4/134 (3%), Rh incompatibility in 1/134 (1%), prematurity in 12/134 (9%) and sepsis neonatorum in 21/134 (16%). The hyperbilirubinaemia was idiopathic in 96/134 (71%) infants. Newborns in Antigua and Barbuda were discharged 3.7 days after their mothers' admission, with 50% discharged prior to 48 hours of age. Early discharge in developed countries has led to increased readmissions for hyperbilirubinaemia. Following the appointment of a dietitian to supervise breast-feeding, admissions for hyperbilirubinaemia fell by 50% by 1998. These data suggest that exclusive breast-feeding and early discharge led to an epidemic of neonatal hyperbilirubinaemia in Antigua and Barbuda.

Sedation of hyperthyroid cats with subcutaneous administration of a combination of alfaxalone and butorphanol.

OBJECTIVE: To evaluate the sedative, respiratory and cardiovascular effects of subcutaneously administered alfaxalone and butorphanol in a group of hyperthyroid cats. DESIGN: A prospective, single-centre observational study. METHODS: Client-owned hyperthyroid cats (n=20) were examined and sedated with alfaxalone (3 mg/kg) and butorphanol (0.2 mg/kg) administered subcutaneously. Sedation scores, heart rate, respiratory rate and blood pressure were measured at 15-min intervals during the 45-min observation period and compared with pre-sedation values. At the end of 45 min, cats were assessed to be adequately sedated for oral administration of iodine-131 if there was minimal resistance and an intact gag reflex. RESULTS: The maximum median sedation score was reached 45 min after injection. The lowest mean heart and respiratory rates and blood pressure values occurred 30 min after injection. Significant decreases were noted in respiratory rates at all three time points (P<0.001). Systolic, diastolic and mean blood pressure measurements were also significantly decreased at 15 and 30 min after injection (P<0.05). CONCLUSION: Subcutaneously administered alfaxalone and butorphanol can be used for sedation in cats undergoing procedures of short duration. Blood pressure should be monitored because of transient decreases observed in some cats. Further studies are required to determine whether the sedative, respiratory and cardiovascular effects are similar in euthyroid cats.

The prevalence, clinical features and association of HLA-B27 in sacroiliitis associated with established Crohn's disease.

BACKGROUND: Sacroiliitis is a recognized complication of Crohn's disease and may occur distinct from progressive ankylosing spondylitis (AS). AIM: To estimate prospectively the prevalence of sacroiliitis in patients with established Crohn's disease, to characterize the clinical features and to correlate these with the presence of HLA-B27. METHODS: All Crohn's disease patients under active follow-up of between 5 and 12 years duration were invited to participate. Patients underwent a clinical evaluation including symptom questionnaire, rheumatological examination and underwent HLA genotyping. Patients then underwent magnetic resonance imaging (MRI) of the sacroiliac joints. The clinical and radiological factors were correlated with HLA-B27 status. RESULTS: 56 patients underwent initial assessment and 44 had MRI scans. Seventeen of 44 (39%) patients had MRI evidence of sacroiliitis, of whom 5 fulfilled the criteria for AS. Symptoms of low back pain were elicited in a majority of these patients--11/17 (65%) compared to 3 of 27 (11%) patients with normal scans (P = 0.003). There were no differences in functional indices with the exception of patients with AS. HLA-B27 was present in seven patients, and all seven had MRI evidence of sacroiliitis, five had AS. CONCLUSIONS: Sacroiliitis is common in patients with established Crohn's disease and in the majority of cases, patients have symptoms of inflammatory low back pain if questioned carefully. HLA-B27 is not associated with isolated sacroiliitis, but is associated with AS. However, possession of HLA-B27 appears to convey a very high risk of developing axial inflammation in Crohn's disease.

Non-B27 MHC associations of ankylosing spondylitis.

Ankylosing spondylitis (AS) has been associated with human leukocyte antigen (HLA)-B27 for over 30 years; however, the mechanism of action has remained elusive. Although many studies have reported associations between AS and other genes in the major histocompatibility complex (MHC) in AS, no conclusive results have emerged. To investigate the contribution of non-B27 MHC genes to AS, a large cohort of AS families and controls were B27 typed and genotyped across the region. Interrogation of the data identified a region of 270 kb, lying from 31 952 649 to 32 221 738 base pairs from the p-telomere of chromosome 6 and containing 23 genes, which is likely to include genes involved with susceptibility to AS.

Disaster: the helper's perspective.

The responses to disaster and death vary enormously, but there is much to suggest that they are not confined to those who are directly affected. The helpers, too, may be "victims" of the disaster, and it is important that their psychological needs are perceived and met. There is an indication that, if this is done, considerable psychological morbidity may be prevented.

The CD19 signal transduction complex of B lymphocytes. Deletion of the CD19 cytoplasmic domain alters signal transduction but not complex formation with TAPA-1 and Leu 13.

CD19 expressed on the surface of B lymphocytes is a key member of a cell surface signal transduction complex that includes TAPA-1, Leu 13 and CD21. The human CD19 protein is composed of 540 amino acids with a cytoplasmic domain of 242 amino acids. Although the cytoplasmic domain of CD19 has no sequence homology with other proteins, the cytoplasmic domain of human, mouse, and guinea pig CD19 is highly conserved suggesting that this region of CD19 is at least partially responsible for signaling activity. In this study, the regions of CD19 required for intermolecular associations and signal transduction were determined by comparing a series of carboxyl-terminal cytoplasmic tail deletion mutants and a CD19/L-selectin chimera with native CD19. CD19 expressed in the human Rex T cell line and the K562 erythroleukemia cell line generated transmembrane signals and also associated with endogenous TAPA-1. Deletion of 95% of the CD19 cytoplasmic domain did not affect the ability of CD19 to be expressed or to associate with TAPA-1. However, replacement of the CD19 transmembrane and cytoplasmic domains with those of L-selectin (CD19-LAM) resulted in the loss of CD19 complex formation, suggesting that the membrane spanning domain is critical for this association. Similarly, the induction of homotypic adhesion through CD19 or truncated CD19 was equivalent, whereas homotypic adhesion was not induced via the CD19-LAM chimera. In addition, the cytoplasmic domain was not necessary for CD19 mAb-mediated growth inhibition or internalization. In contrast, the CD19 cytoplasmic domain was required for optimal mAb-induced increases in [Ca2+]i in CD19 cDNA-transfected Rex cells. Thus, the CD19 cytoplasmic domain is responsible for the induction of increased [Ca2+]i, and the transmembrane region is required for cell surface associations with the other members of the CD19 complex and most signaling events. Therefore, mAb binding to CD19 is likely to initiate multiple intracellular signal transduction cascades either through CD19 directly, or through other members of the CD19 complex.

Randomized placebo controlled trial of lofexidine hydrochloride for chronic pelvic pain in women.

BACKGROUND: We hypothesised that the orally-active alpha(2)-adrenoceptor agonist lofexidine hydrochloride would ameliorate chronic pelvic pain in women. METHODS: A randomized placebo-controlled parallel group trial was undertaken in the University Hospital Gynaecology Clinic. Women with pelvic pain of at least 6 months duration were eligible, and were randomized using a sealed envelope system to receive up to 600 mg lofexidine hydrochloride twice daily over 8 weeks or placebo. Outcome measures were summary and daily diary visual analog scales for pain (VAS) and a 5 point self rating scale. RESULTS: 9/19 women randomized to lofexidine completed the study compared to 14/20 of those randomized to placebo. Intention-to-treat analysis showed that 4/19 in the lofexidine group achieved 50% or greater reduction in VAS compared with 8/20 in the placebo group (OR 2.5, 95% CI 0.6--10.3). Summary and diary VAS were closely correlated. CONCLUSIONS: Within the limits of a small study with power to detect only a substantial effect, we conclude that lofexidine hydrochloride is not effective for the treatment of chronic pelvic pain.

The CD19/CD21 signal transducing complex of human B lymphocytes includes the target of antiproliferative antibody-1 and Leu-13 molecules.

CD19 is a member of the Ig superfamily expressed on the surface of B lymphocytes that may be involved in the regulation of B cell function. Immunoprecipitation studies with B cell lines solubilized by digitonin have shown CD19 to be part of a multimolecular complex that includes CD21 (CR2) and other unidentified proteins. In this study, two of the CD19-associated proteins were identified as TAPA-1, which is expressed on most cell types, and Leu-13, which is expressed on subsets of lymphoid cells. TAPA-1 and Leu-13 are physically associated in many cell lineages. CD19 and CD21 mAb each specifically coprecipitated proteins of the same size as those precipitated by TAPA-1 and Leu-13 mAb from B cell lines and cDNA-transfected K562 cell lines. Western blot analysis with a TAPA-1 mAb verified the identity of TAPA-1 in CD19 and CD21 immunoprecipitated materials. In addition, when TAPA-1 or Leu-13 were crosslinked and patched on the cell surface, all of the CD19 comigrated with TAPA-1 and some of the CD19 comigrated with Leu-13. Furthermore, mAb binding to CD19, CD21, TAPA-1, and Leu-13 on B cell lines induced similar biologic responses, including the induction of homotypic adhesion, inhibition of proliferation, and an augmentation of the increase in intracellular [Ca2+] induced by suboptimal cross-linking of surface Ig on B cell lines. Together, these data suggest that TAPA-1 and Leu-13 are broadly expressed members of a signal transduction complex in which lineage-specific proteins, such as CD19 and CD21, provide cell-specific functions.