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Biomedical subjects

Hal M Hoffman

Publications and source records attributed to Hal M Hoffman.

13 recordsLinked to original sources
PubMed2006

Anakinra prevents symptoms of familial cold autoinflammatory syndrome and Raynaud's disease.

OBJECTIVE: Familial cold autoinflammatory syndrome (FCAS) is a rare, hereditary disorder characterized by cold-induced inflammation. We describe the successful longterm treatment of a patient with FCAS with anakinra, an interleukin 1 receptor antagonist (IL-1Ra). The remarkable response of FCAS and associated Raynaud's disease in this patient suggests that IL-1 is an important mediator of these inflammatory diseases. Our report supports increasing evidence that anakinra plays an important role in the treatment of select chronic inflammatory diseases.

Cold Temperature↗
PubMed2006

A severe case of chronic infantile neurologic, cutaneous, articular syndrome treated with biologic agents.

In this report we describe a case of severe chronic infantile neurologic, cutaneous, articular (CINCA) syndrome with a novel G307V cryopyrin mutation and all of the characteristic clinical and laboratory features of this autoinflammatory disease. There was no clear response to standard therapies, including human interleukin-1 (IL-1) receptor antagonist (anakinra) and soluble tumor necrosis factor receptor (etanercept). The patient finally had a partial clinical response (reduction in fever and irritability) and complete laboratory response (improved C-reactive protein and serum amyloid A levels) to humanized anti-IL-6 receptor antibody (MRA), but died from congestive heart failure and interstitial pneumonia 2 months after initiation of therapy. We serially measured the serum cytokine levels and expression of NF-kappaB activation in the patient's peripheral blood mononuclear cells before and during consecutive therapies. Pathologic examination of autopsy specimens was also performed. This case illustrates the continued difficulty in management of patients with CINCA syndrome and the complexity of the inflammatory pathways in this disorder.

Antibodies, Anti-Idiotypic↗
PubMed2006

CATERPILLERs, pyrin and hereditary immunological disorders.

The newly described CATERPILLER family (also known as NOD-LRR or NACHT-LRR) is comprised of proteins with a nucleotide-binding domain and a leucine-rich region. This family has gained rapid prominence because of its demonstrated and anticipated roles in immunity, cell death and growth, and diseases. CATERPILLER proteins are structurally similar to a subgroup of plant-disease-resistance (R) proteins and to the apoptotic protease activating factor 1 (APAF1). They provide positive and negative signals for the control of immune and inflammatory responses, and might represent intracellular sensors of pathogen products. Most importantly, they are genetically linked to several human immunological disorders.

Carrier Proteins↗
PubMed2005

IL-converting enzyme/caspase-1 inhibitor VX-765 blocks the hypersensitive response to an inflammatory stimulus in monocytes from familial cold autoinflammatory syndrome patients.

Familial cold autoinflammatory syndrome (FCAS) and the related autoinflammatory disorders, Muckle-Wells syndrome and neonatal onset multisystem inflammatory disease, are characterized by mutations in the CIAS1 gene that encodes cryopyrin, an adaptor protein involved in activation of IL-converting enzyme/caspase-1. Mutations in cryopyrin are hypothesized to result in abnormal secretion of caspase-1-dependent proinflammatory cytokines, IL-1beta and IL-18. In this study, we examined cytokine secretion in PBMCs from FCAS patients and found a marked hyperresponsiveness of both IL-1beta and IL-18 secretion to LPS stimulation, but no evidence of increased basal secretion of these cytokines, or alterations in basal or stimulated pro-IL-1beta levels. VX-765, an orally active IL-converting enzyme/caspase-1 inhibitor, blocked IL-1beta secretion with equal potency in LPS-stimulated cells from FCAS and control subjects. These results further link mutations in cryopyrin with abnormal caspase-1 activation, and support the clinical testing of caspase-1 inhibitors such as VX-765 in autoinflammatory disorders.

Adult↗
PubMed2005

Staphylococcus aureus golden pigment impairs neutrophil killing and promotes virulence through its antioxidant activity.

Golden color imparted by carotenoid pigments is the eponymous feature of the human pathogen Staphylococcus aureus. Here we demonstrate a role of this hallmark phenotype in virulence. Compared with the wild-type (WT) bacterium, a S. aureus mutant with disrupted carotenoid biosynthesis is more susceptible to oxidant killing, has impaired neutrophil survival, and is less pathogenic in a mouse subcutaneous abscess model. The survival advantage of WT S. aureus over the carotenoid-deficient mutant is lost upon inhibition of neutrophil oxidative burst or in human or murine nicotinamide adenine dinucleotide phosphate oxidase-deficient hosts. Conversely, heterologous expression of the S. aureus carotenoid in the nonpigmented Streptococcus pyogenes confers enhanced oxidant and neutrophil resistance and increased animal virulence. Blocking S. aureus carotenogenesis increases oxidant sensitivity and decreases whole-blood survival, suggesting a novel target for antibiotic therapy.

Abscess↗
PubMed2004

Structural, expression, and evolutionary analysis of mouse CIAS1.

Mutations in the human CIAS1 (hCIAS1) gene have been identified in a continuum of inflammatory disorders including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal onset multisystem inflammatory disease (NOMID). CIAS1 codes for the protein Cryopyrin, which appears to play a role in innate immune function by regulating the production of proinflammatory cytokines. Human and mouse Cryopyrin are highly conserved and consist of three functional domains including a pyrin domain, an NACHT domain, and a leucine-rich repeat (LRR) domain that are characteristics of the NALP family of proteins. The pyrin and NACHT domains of Cryopyrin and other NALP proteins are highly conserved among primate and nonprimate mammals, suggesting purifying selection throughout mammalian evolution. Cryopyrin expression is also very similar in human and mouse with mouse CIAS1 mRNA expression found primarily in peripheral blood leukocytes consistent with the postulated inflammatory function. We also detected significant expression in mouse eye and skin tissue, which is consistent with symptoms observed in human Cryopyrin-associated diseases.

Amino Acid Sequence↗
PubMed2004

The spectrum of acquired and familial cold-induced urticaria/urticaria-like syndromes.

Acquired cold urticaria syndromes represent one of the more common forms of physical urticaria. The syndromes are heterogenous, and a diagnostic classification is presented to facilitate collation for future studies. Acquired cold urticaria represents an excellent reproducible in vivo model to investigate the mechanisms of urticaria. The discussion includes clinical manifestations, laboratory features, pathogenesis, and management of these disorders. A description of familial types, particularly familial cold auto-inflammatory syndrome (FCAS) that is manifested by cold-evoked signs and symptoms of chronic inflammation, is included. FCAS historically has been included with acquired cold urticaria, even though the exanthem of FCAS is maculopapular caused by leukocytic infiltration. FCAS has become an important investigative syndrome, as it represents a reproducible in vivo model of chronic inflammation.

Cold Temperature↗
PubMed2003

A large kindred with familial cold autoinflammatory syndrome.

BACKGROUND: Familial cold autoinflammatory syndrome (FCAS), formerly known as familial cold urticaria, is a rare condition characterized by fever, rash, and arthralgias elicited by exposure to cold. Recently, mutations responsible for FCAS were identified in a novel gene (CIAS1), making it possible to confirm the diagnosis in most patients. OBJECTIVE: We present a summary of clinical data from a large family with FCAS to further define the characteristics of the disorder and to validate previously proposed clinical criteria. METHODS: A total of 73 participants were evaluated by interview and questionnaire, including 36 affected individuals. Responses from the questionnaire were analyzed and comparisons of proportions were made using the Z test. DNA was isolated and genotyping was performed on all subjects. Affected haplotypes (genotype patterns) were identified and used to confirm the diagnosis. Sequencing of the CIAS1 gene was performed in selected patients to confirm the mutation. RESULTS: The prevalence of rash, fever/chills, joint complaints, nausea, headache, and thirst were not significantly different from previously reported proportions. There was statistically significant differences in conjunctivitis, sweating, and drowsiness with alpha = 0.01. The mean temperature required to produce symptoms was 22 degrees C, and the average earliest onset of symptoms after exposure was 1.5 hours. CONCLUSIONS: Applying the proposed clinical criteria, 41% of affected subjects met all six criteria, 90% met five criteria, and 100% met four criteria for FCAS. None of the unaffected subjects met more than two criteria. Using a threshold of 4 of 6 clinical criteria, the data support the diagnostic validity of the proposed clinical criteria.

Adolescent↗
PubMed2002

The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy.

Muscle cells respond to mechanical stretch stimuli by triggering downstream signals for myocyte growth and survival. The molecular components of the muscle stretch sensor are unknown, and their role in muscle disease is unclear. Here, we present biophysical/biochemical studies in muscle LIM protein (MLP) deficient cardiac muscle that support a selective role for this Z disc protein in mechanical stretch sensing. MLP interacts with and colocalizes with telethonin (T-cap), a titin interacting protein. Further, a human MLP mutation (W4R) associated with dilated cardiomyopathy (DCM) results in a marked defect in T-cap interaction/localization. We propose that a Z disc MLP/T-cap complex is a key component of the in vivo cardiomyocyte stretch sensor machinery, and that defects in the complex can lead to human DCM and associated heart failure.

Adult↗
PubMed2002

Fine structure mapping of CIAS1: identification of an ancestral haplotype and a common FCAS mutation, L353P.

Familial cold autoinflammatory syndrome (FCAS) is an autosomal dominant inflammatory disease with a high degree of penetrance that is characterized by episodes of rash, arthralgia, fever, conjunctivitis, and leukocytosis after generalized exposure to cold. FCAS was previously mapped to a 10-cM region on chromosome 1q44, and subsequently the gene ( CIAS1) responsible for FCAS was identified. In this paper, we describe the physical and genetic mapping of the FCAS locus, and we report a large ancestral haplotype and a new disease-causing mutation. A BAC contig of approximately 3 Mb was developed and subsequently used for high throughput sequencing. We identified a critical region of 4 cM using rare crossover events in four large North American FCAS families. An unusually large shared haplotype (40 cM) was identified in three of the four families. We found a single heterozygous missense mutation (T1058C=L353P) in exon 3 of CIAS1 in all four families that is responsible for the large majority of FCAS cases described in the literature. We also report a comprehensive list of intragenic single nucleotide polymorphisms. The data provided here will assist others researching the 1q44 region and will aid clinicians in the diagnosis of FCAS.

Autoimmune Diseases↗
PubMedDate not supplied

Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist.

BACKGROUND: Familial cold autoinflammatory syndrome (FCAS) is an autosomal dominant disorder characterised by recurrent episodes of rash, arthralgia, and fever after cold exposure. The genetic basis of this disease has been elucidated. Cryopyrin, the protein that is altered in FCAS, is one of the adaptor proteins that activate caspase 1, resulting in release of interleukin 1. METHODS: An experimental cold challenge protocol was developed to study the acute inflammatory mechanisms occurring after a general cold exposure in FCAS patients and to investigate the effects of pretreatment with an antagonist of interleukin 1 receptor (IL-1Ra). ELISA, real-time PCR, and immunohistochemistry were used to measure cytokine responses. FINDINGS: After cold challenge, untreated patients with FCAS developed rash, fever, and arthralgias within 1-4 h. Significant increases in serum concentrations of interleukin 6 and white-blood-cell counts were seen 4-8 h after cold challenge. Serum concentrations of interleukin 1 and cytokine mRNA in peripheral-blood leucocytes were not raised, but amounts of interleukin 1 protein and mRNA were high in affected skin. IL-1Ra administered before cold challenge blocked symptoms and increases in white-blood-cell counts and serum interleukin 6. INTERPRETATION: The ability of IL-1Ra to prevent the clinical features and haematological and biochemical changes in patients with FCAS indicates a central role for interleukin 1beta in this disorder. Involvement of cryopyrin in activation of caspase 1 and NF-kappaB signalling suggests that it might have a role in many chronic inflammatory diseases. RELEVANCE TO PRACTICE: These findings support a new therapy for a disorder with no previously known acceptable treatment. They also offer insights into the role of interleukin 1beta in more common inflammatory diseases.

Acute Disease↗