GB virus C infection in patients with primary antibody deficiency

Sera from 77 patients with common variable immunodeficiency (CVID) were tested for GB virus C (GBV-C) RNA, because they are prone to unexplained chronic hepatitis, and from 28 patients with X-linked agammaglobulinemia (XLA) who have a similar primary antibody deficiency but are not prone to hepatitis. Eight CVID and 8 XLA patients were positive; 6 positive CVID and 3 XLA patients had abnormal liver enzymes, explained in 3 by either hepatitis B or C virus infection. Most patients tested had antibodies to the E2 antigen of GBV-C, apparently passively acquired from their immunoglobulin therapy. The high prevalence of GBV-C viremia in CVID and XLA patients is probably explained by their long-term exposure to blood products. Our data indicate that GBV-C does not cause chronic hepatitis in immunocompromised XLA patients and is not the cause of chronic non-B or -C hepatitis in the majority of CVID patients.     

TNF and lymphotoxin-alpha polymorphisms associated with common variable immunodeficiency: role in the pathogenesis of granulomatous disease

A subgroup of common variable immunodeficiency (CVID) patients have distinct clinical features, particularly granulomata splenomegaly, characteristic blood lymphocyte phenotype, and elevated circulating TNF levels. To investigate the genetic basis for this phenotype, 150 CVID patients and 200 controls were genotyped for six biallelic TNF and lymphotoxin-alpha (LT alpha) polymorphisms and eight class I and II HLA loci using PCR and sequence specific primers (PCR-SSP) sequence-specific primers. Clinical and immunophenotypic data were collected for 90 patients to examine associations with CVID patient subgroups. The presence of granulomata (22% of patients) was strongly associated with splenomegaly, T and B lymphopenia, reduced CD4+ CD45RA+ T cells, and CD8+ CD57+ lymphocytosis, confirming the concept of a subgroup of patients with distinct clinical and laboratory features. The uncommon TNF +488A allele was strongly associated with this subgroup (p = 0.0005). The association between "granulomatous" CVID and TNF +488A was independent of HLA class I and II associations. We postulate that the presence of the TNF +488A allele, or alleles in linkage disequilibrium with it, contributes to the high levels of TNF and granulomatous complications characteristic of this subgroup of patients.     

Oxygen-evolving diatom thylakoid membranes

BACKGROUND: A common genetic basis for IgA deficiency (IgAD) and common variable immunodeficiency (CVID) is suggested by their occurrence in members of the same family and the similarity of the underlying B cell differentiation defects. An association between IgAD/CVID and HLA alleles DR3, B8, and A1 has also been documented. In a search for the gene(s) in the major histocompatibility complex (MHC) that predispose to IgAD/CVID, we analyzed the extended MHC haplotypes present in a large family with 8 affected members. MATERIALS AND METHODS: We examined the CVID proband, 72 immediate relatives, and 21 spouses, and determined their serum immunoglobulin concentrations. The MHC haplotype analysis of individual family members employed 21 allelic DNA and protein markers, including seven newly available microsatellite markers. RESULTS: Forty-one (56%) of the 73 relatives by common descent were heterozygous and nine (12%) were homozygous for a fragment or the entire extended MHC haplotype designated haplotype 1 that included HLA- DR3, -C4A-0, -B8, and -A1. The remarkable prevalence of haplotype 1 was due in part to marital introduction into the family of 11 different copies of the haplotype, eight sharing 20 identical genotype markers between HLA-DR3 and HLA-B8, and three that contained fragments of haplotype 1. CONCLUSION: Crossover events within the MHC indicated a susceptibility locus for IgAD/CVID between the class III markers D821/D823 and HLA-B8, a region populated by 21 genes that include tumor necrosis factor alpha and lymphotoxins alpha and beta. Inheritance of at least this fragment of haplotype 1 appears to be necessary for the development of IgAD/CVID in this family.     

Compartment syndromes of the hand

We retrospectively reviewed the records of nineteen patients who had been managed with fasciotomy because of compartment syndrome of the hand. The patients were five months to sixty-seven years old and included ten adults and nine children. Seventeen patients were followed for an average of twenty-one months (range, one to fifty-eight months), one patient was lost to follow-up after discharge, and one patient died four days postoperatively. All of the patients had a tense, swollen hand and elevated pressure in at least one interosseous compartment. Eight patients also had a compartment syndrome of the forearm. The compartment syndromes developed after intravenous injections (eleven patients); after a gunshot wound, a crush injury, or a complication related to the use of an arterial line (two patients each); and after a complication related to an arthrodesis of the wrist or a crush injury due to prolonged pressure on the upper extremity secondary to a drug overdose (one patient each). Fifteen patients had an obtunded sensorium-either because of a serious illness or injury or secondary to prolonged anesthesia-when the compartment syndrome was recognized. In thirteen of these patients, including eight children and five adults, the compartment syndrome developed because of a complication related to the intravenous or intra-arterial administration of drugs. Carpal tunnel release and decompression of the involved compartments led to a satisfactory result for thirteen of the seventeen patients who were followed. The remaining four patients (including two children who had an amputation, one child who had impaired function of the hand secondary to brain damage, and one adult who had extensive involvement of the forearm and complete loss of function of the hand) had a poor result. All four of these patients had been obtunded when the compartment syndrome developed. The treating physician should maintain a high index of suspicion for a compartment syndrome of the hand when managing seriously ill, obtunded patients-particularly children-who are receiving multiple intravenous or intra-arterial injections.     

Acute compartment syndrome of the thigh after joint replacement with anticoagulation

We describe three patients with a compartment syndrome of the thigh, two after total hip replacement and one after total knee replacement. Two of the patients were fully anticoagulated. A compartment syndrome of the thigh is a rare, but important complication of joint replacement surgery if patients are receiving anticoagulants. Close observation is needed and when indicated monitoring of the intracompartmental pressure should be done. Early recognition of the signs and symptoms of an acute compartment syndrome and knowledge of the anatomy of the compartments of the thigh will help in the diagnosis and treatment of this potentially devastating complication.     

Compartment syndromes in obtunded patients

A high index of suspicion for a compartment syndrome in the upper extremity should be maintained in all obtunded patients who are at risk for the condition. Obtunded patients are those with a dulled or altered physical or mental status secondary to injury, illness, or anesthesia; those with diminished or absent sensation in the upper extremity because of nerve injury or anesthesia; and those whose ability to communicate is impeded, such as infants and young children and the mentally ill or disabled. These patients represent a vulnerable group whose inability to demonstrate the hallmark symptoms and signs of the syndrome puts them in jeopardy of a late diagnosis of a compartment syndrome and its potentially devastating sequelae. The most likely causes of a compartment syndrome in this population are skeletal or soft-tissue trauma, prolonged limb compression, thrombolytic therapy after myocardial infarction, arterial or intravenous fluid administration, and upper extremity Surgery. Whenever a compartment syndrome of the hand, forearm, or upper arm is suspected, the obtunded patient should be examined closely and frequently, and any changes over time should be documented carefully. Intracompartmental pressure measurement provides a useful adjunct to the physical examination and history in these patients and may be diagnostic if other symptoms and signs are obscured. Once the compartment syndrome is diagnosed, emergent fasciotomy is indicated. To avoid a loss of function in the obtunded patient, special care must be taken postoperatively to assure that early motion exercises are carried out.     

Enhanced interaction of HLA-DM with HLA-DR in enlarged vacuoles of hereditary and infectious lysosomal diseases

Following biosynthesis, class II MHC molecules are transported through a lysosome-like compartment, where they acquire antigenic peptides for presentation to T cells at the cell surface. This compartment is characterized by the presence of HLA-DM, which catalyzes the peptide loading process. Here we report that the morphology and function of the class II loading compartment is affected in diseases with a phenotypic change in lysosome morphology. Swollen lysosomes are observed in cells from patients with the hereditary immunodeficiency Chediak-Higashi syndrome and in cells infected with Coxiella burnetii, the rickettsial organism that causes Q fever. In both disease states, we observed that HLA-DR and HLA-DM accumulate in enlarged intracellular compartments, which label with the lysosomal marker LAMP-1. The distribution of class I MHC molecules was not affected, localizing disease effects to the endocytic pathway. Thus, cellular mechanisms controlling lysosome biogenesis also affect formation of the class II loading compartment. Analysis of cell surface class II molecules revealed that their steady-state levels were not reduced on diseased cells. However, in both disease states, enhanced interaction between HLA-DR and HLA-DM was detected. In the Chediak-Higashi syndrome cells, this correlated with more efficient removal of the CLIP peptide. These findings suggest a mechanism for perturbation of Ag presentation by class II molecules and consequent immune deficiencies in both diseases.     

CD40 ligand expression deficiency in a female carrier of the X-linked hyper-IgM syndrome as a result of X chromosome lyonization

We report on the case of a girl with an immune deficiency characterized by recurrent infections of the upper and lower respiratory tract, low IgG and IgA serum levels as well as deficiency of the in vivo antibody response. Since this patient is the sister of a boy affected with a hyper-IgM syndrome due to a defect in CD40 ligand (CD40L) expression, the involvement of CD40L in this phenotypic expression was investigated. A very low fraction of activated T cells (5%) in this female patient expressed CD40L. This resulted from the presence of a heterozygous CD40L nonsense mutation associated with a skewed pattern of X chromosome inactivation as determined by methylation pattern analysis. Although carriers of X-linked hyper-IgM are considered to be asymptomatic, this study indicates that extreme lyonization of the normal X can lead to a mild expression of the hyper-IgM syndrome which is similar to common variable immune deficiency (CVID). Therefore, it is possible that some cases of CVID in females represent partial deficiency of CD40L expression in carriers of the CD40L mutation.     

Iliac artery ischemic: analysis of risks for ischemic complications

Risk factors for lower extremity ischemic complications (ICs) following iliac arterial injuries have not been addressed. Patients with penetrating iliac artery injuries over a 15-year period were reviewed. IC was defined as compartment syndrome with or without tissue loss. Patients with iliac artery repair who developed ICs were compared with those without ICs (excluding early deaths from hemorrhagic shock). Comparison included demographics, severity of shock, physical examination, and operative findings. There were 94 arterial injuries in 80 patients (34 common iliac, 23 internal iliac, and 37 external iliac). There were 26 deaths (33%), and 3 patients were excluded for technical reasons. Of the 51 who underwent arterial reconstruction, 34 had no ischemia, whereas 17 (33%) had ICs (9 with tissue loss and 8 with compartment syndrome only). Immediate fasciotomies were performed in 6 of the IC patients due to the early recognition of compartment syndrome; 1 required amputation from the profound ischemia. Delayed recognition of compartment syndrome in the remaining 11 IC patients resulted in eight amputations (P < 0.05). We conclude that ICs following iliac arterial injuries significantly correlate with shock as indicated by systemic pH, lactate and transfusion requirements, and a preoperative pulseless extremity. In these patients, close monitoring of compartment pressures is necessary, and immediate fasciotomies should be strongly considered.     

Rate of HIV-1 decline following antiretroviral therapy is related to viral load at baseline and drug regimen

OBJECTIVES AND DESIGN: The dynamics uf viral decline following the initiation of antiretroviral treatment were studied in 29 HIV-1-infected patients participating in a two-arm trial comparing immediate (group A: ritonavir, zidovudine and lamivudine) and delayed (group B: ritonavir supplemented by zidovudine and lamivudine on day 21) triple therapy. Parameters underlying viral dynamics were estimated using mathematical models tailored to these treatment protocols. RESULTS: The decline in plasma HIV-1 density between day 0 and 21 was steeper in group A (-2.27+/- 0.46 log10) than group B (-1.87+/-0.56 log10). In a subset of patients amenable to full mathematical analysis, a short-lived productively infected cell compartment (producing approximately 97% of total virions) decayed with a half-life of 1.0-2.5 days, whereas a long-lived infected cell compartment decayed with a half-life of 18.8-32.8 days. Estimates for the time for the elimination of virus from these two cell populations ranged from 474 to 802 days. The rate of loss of productively infected CD4+ T cells was positively correlated with baseline viral load in group A and in the combined dataset. CONCLUSIONS: These results suggest that HIV-infected cell populations may have a faster turnover in patients with higher viral loads due to higher infection rate parameters, higher rates of virus production, or lower virus clearance rates.     

Common variable immunodeficiency with CD4+ T lymphocytopenia and overproduction of soluble IL-2 receptor associated with Turner's syndrome and dorsal kyphoscoliosis

An unusual combination of common variable immunodeficiency (CVID) and Turner's syndrome in a Saudi woman aged 20 years is presented. In addition to panhypogammaglobulinaemia, the patient had CD4+ T lymphocytopenia; however, there was evidence of in vivo activation of T cells and overproduction of soluble interleukin 2 receptor in culture supernate. Mantoux test was positive, but lymphoblastic response to non-specific mitogen was impaired. Immunogenetically the patient was HLA-DR3 positive and karyotypically she was a mosaic (45XO/46XX) with ring X chromosome (46Xr(X)). The presence of severe kyphoscoliosis was possibly related to ring X chromosome. This case highlights the grave consequences of the delayed diagnosis of immunodeficiency and emphasises the heterogeneous nature of CVID.     

Involvement of MIIC-like late endosomes in B cell receptor-mediated antigen processing in murine B cells

Currently, the involvement of classical vs novel endocytic compartments in the phenomenon of B cell receptor (BCR)-mediated Ag processing is a matter of considerable debate. In murine B cells, class II vesicles (CIIV) represent a novel endocytic compartment involved in BCR-mediated Ag processing and class II peptide loading. Alternatively, in human B cells, the MHC class II-enriched compartment (MIIC) represents a lysosome (L)-like endocytic compartment that appears to be involved in this process. Presently, the relationship between CIIV, MIIC, and classical endosomes and L remains to be determined. Using density gradient centrifugation, a subcellular compartment morphologically and immunologically similar to human MIIC has been identified, isolated, and characterized in murine B cells. These MIIC-like vesicles represent a population of class II-positive late endosomes (LE) and are distinct from CIIV. MIIC-like LE are uniquely marked by the thiol protease cathepsin B, and along with mature L, appear to be the major repository of DM molecules in these cells. Importantly, both MIIC-like LE and CIIV isolated from Ag-pulsed B cells contain BCR-internalized Ag as well as antigenic peptide-class II complexes.     

CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome

The ligand for CD40 (CD40L) is a membrane glycoprotein on activated T cells that induces B cell proliferation and immunoglobulin secretion. Abnormalities in the CD40L gene were associated with an X-linked immunodeficiency in humans [hyper-IgM (immunoglobulin M) syndrome]. This disease is characterized by elevated concentrations of serum IgM and decreased amounts of all other isotypes. CD40L complementary DNAs from three of four patients with this syndrome contained distinct point mutations. Recombinant expression of two of the mutant CD40L complementary DNAs resulted in proteins incapable of binding to CD40 and unable to induce proliferation or IgE secretion from normal B cells. Activated T cells from the four affected patients failed to express wild-type CD40L, although their B cells responded normally to wild-type CD40L. Thus, these CD40L defects lead to a T cell abnormality that results in the failure of patient B cells to undergo immunoglobulin class switching.     

Bilateral ureteral obstruction and renal failure caused by massive retroperitoneal hematoma: is there a pelvic compartment syndrome analogous to abdominal compartment syndrome?

OBJECTIVES: To describe an intrapelvic compartment syndrome analogous to abdominal compartment syndrome and to characterize its diagnosis and treatment. DESIGN: Retrospective analysis. SETTING: Level I trauma center. PATIENTS: Three patients with pelvic ring or acetabular fractures presented with bilateral ureteral obstruction, renal organ failure, and anuria due to direct compression of both ureters in the true pelvis by a massive retroperitoneal hematoma. INTERVENTION: Surgical therapy consisted of fracture stabilization, decompression of the retroperitoneal space, and evacuation of the hematoma. Persistent isolated bleeding points were either embolized preoperatively or ligated. RESULTS: After decompression, all three patients promptly recovered their renal organ function. CONCLUSION: An intrapelvic compartment syndrome can be defined as bilateral ureteral obstruction and renal failure caused by a massive intrapelvic hematoma with increased retroperitoneal pressure. Diagnostic differentiation of anuria in patients with pelvic ring or acetabular fractures must include intrapelvic compartment syndrome. Early diagnosis and treatment are mandatory.     

Immunoglobulin deficient mice generated by gene targeting as models for studying the immune response

B cell deficient animals obtained by various strategies of gene targeting were used to study the B cell development and examine the role of different immune compartments in the immune response to microbes. Study of muMT, JHD, lambda 5T and JHT models of B cell deficiency, was essential in order to understand the role of pre-B cell receptor in B cell development, allelic exclusion and variable gene rearrangement regulation. In the immune response to influenza virus, a protective role of T cells in a total absence of B cell compartment, was revealed by studying the JHD -/- model. Further, it was established that a T cell compartment is sufficient to mediate the recovery from influenza infection. Examination of immune response in muMT and JHD models of definitive B cell deficiency to various blood stage Plasmodia species, showed that whereas B cells are not required for recovery from infection with P. chabaudi adami, P. vinckei petteri and P. chabaudi chabaudi (CB), B cell compartment is important in the later stages of infection with P. chabaudi chabaudi (AS). Studies carried out in muMT model suggested a possible role for T gamma delta subpopulation in the immune response to blood stage malaria parasite. B cell deficiency models are valuable for understanding the normal and pathological immune response. Studies carried out in muMT model indicated that T cell responses are not significantly affected in the absence of B cells. These data can neither rule out a role for B cells in T cell priming, nor in triggering an effective T cell help for humoral response. Study of double homozygous mice deficient for B cells and FAS or IL-2 gene, pinpointed the role of B cells in pathogenesis of lupus-like nephritis and vasculitis from lpr mouse and in hemolytic anemia from IL-2 -/- mouse model, respectively.     

Antigen-driven clonal proliferation of B cells within the target tissue of an autoimmune disease. The salivary glands of patients with Sj?gren's syndrome

Structures resembling germinal centers are seen in the salivary glands of patients with Sj?gren's syndrome, but it is not known whether the microenvironment of these cell clusters is sufficient for the induction of a germinal center response. Therefore, we cloned and sequenced rearranged Ig V genes expressed by B cells isolated from sections of labial salivary gland biopsies from two Sj?gren's syndrome patients. Rearranged V genes from B cells within one cell cluster were polyclonal and most had few somatic mutations. Two adjacent clusters from another patient each contained one dominant B cell clone expressing hypermutated V genes. None of the rearranged V genes was found in both clusters, suggesting that cells are unable to migrate out into the surrounding tissue and seed new clusters. The ratios of replacement to silent mutations in the framework and complementarity determining regions suggest antigen selection of high-affinity mutants. These results show that an antigen-driven, germinal center-type B cell response is taking place within the salivary glands of Sj?gren's syndrome patients. In view of the recent demonstration of a germinal center response within the rheumatoid synovial membrane and the existence of similar structures in the target tissues of other autoimmune diseases, we propose that germinal center- type responses can be induced in the nonlymphoid target tissues of a variety of autoimmune diseases.     

Prevention of abdominal compartment syndrome by absorbable mesh prosthesis closure

OBJECTIVE: To determine whether prevention of the abdominal compartment syndrome after celiotomy for trauma justifies the use of absorbable mesh prosthesis closure in severely injured patients. DESIGN: Retrospective analysis of case series from July 1, 1989, to July 31, 1996. SETTING: University-based level I trauma center. PATIENTS: Seventy-three consecutive trauma patients requiring celiotomy who received absorbable mesh prosthesis closure and 73 control patients matched for injury severity and trauma type who received celiotomy without a mesh prosthesis closure. INTERVENTIONS: Absorbable mesh prosthesis closure was used in cases of excessive fascial tension, abdominal compartment syndrome, necrotizing fasciitis, traumatic defect, or planned reoperation. MAIN OUTCOME MEASURES: Demographics, Injury Severity Score, Abdominal Trauma Index, highest abdominal Abbreviated Injury Scale score, number of abdominal/pelvic injuries, highest head Abbreviated Injury Scale score, shock, indication for mesh closure, complications, number of operations and time required for closure, days in the intensive care unit, length of stay, and mortality were determined. The highest abdominal Abbreviated Injury Scale score was multiplied by the number of abdominal/pelvic injuries to calculate the abdominal pelvic trauma score. RESULTS: Group 1 consisted of 47 patients who received mesh at initial celiotomy, and group 2, 26 patients who received mesh at a subsequent celiotomy. These 2 groups were statistically similar in demographics, injury severity, and mortality. However, group 2 had a significantly higher incidence of postoperative abdominal compartment syndrome (35% vs 0%), necrotizing fasciitis (39% vs 0%), intra-abdominal abscess/peritonitis (35% vs 4%), and enterocutaneous fistula (23% vs 11%) compared with group 1 (P < .001). Group 1 patients with preoperative abdominal compartment syndrome had more abdominal/ pelvic injuries and higher abdominal trauma index than matched controls (P < .05). There was a trend toward higher abdominal pelvic trauma score in patients who developed abdominal compartment syndrome. The Pearson coefficient of correlation between the abdominal trauma index and the more easily calculated abdominal pelvic trauma score was 0.91 (P < .001). CONCLUSION: The use of absorbable mesh prosthesis closure in severely injured patients undergoing celiotomy was effective in treating and preventing the abdominal compartment syndrome.     

Compartment syndrome of the buttock following a total hip arthroplasty

An elevation of the interstitial pressure in a closed osseofascial compartment results in compartment syndrome. This may be caused by a decrease in compartment volume or an increase in compartment contents. The gluteal compartment syndrome is rare. Because the gluteal region has a large volume, this compartment requires a massive increase in content to cause a compartment syndrome. Also, this compartment blends anatomically with the muscles of the thigh, allowing extravasation of blood outside the compartmental envelope. This case report is of a patient whose medial circumflex femoral artery was severed during a total hip arthroplasty through a posterior approach leading to compartment syndrome of the buttock. Although this clinical presentation has not been described as compartment syndrome, one similar presentation was described in the literature.     

Cytokines in the aspect of pathogenesis and therapy of acute radiation sickness

The statement about dominating role of stem cell failure (exhaustion) in acute radiation bone marrow syndrome outcome needs to be changed. Cytokine-producing cells lacking reactivity that prevent usage of stem cell compartment reserves can play important role in immunohemopoiesis radiation damage.