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Biomedical subjects

Tammy M Martin

Publications and source records attributed to Tammy M Martin.

At least 19 recordsLinked to original sources
PubMed2006

Human endothelial cells express NOD2/CARD15 and increase IL-6 secretion in response to muramyl dipeptide.

Mutations in the human NOD2/CARD15 gene cause Blau syndrome, an autoinflammatory disorder involving the joints, skin and eyes. Insights into the mechanism of this association may be gained by a further understanding of where NOD2 is expressed. The objective of this study was to analyze ocular endothelial cells for NOD2 expression. Human ocular tissue was analyzed by immunohistology using anti-NOD2 antisera. RNA isolated from iris, choroid and endothelial cell lines was analyzed by reverse transcription-PCR and real-time quantitative PCR. Gene regulation was studied by treating endothelial cells with TNF-alpha and IFN-gamma. Functional responses were assessed by measuring IL-6 release from endothelial cells treated with muramyl dipeptide (MDP), synthetic lipopeptide (Pam3CSK4) and lipopolysaccharide (LPS). Immunohistological analysis revealed staining of endothelial cells in the uveal tract. NOD2 expression was detected in primary ocular endothelial cell cultures, and levels increased in response to inflammatory cytokines. Endothelial cells from choroid demonstrated enhanced release of IL-6 in response to MDP, and synergy was observed following treatment with MDP and either Pam3CSK4 or LPS. The observations that endothelial cells express NOD2, upregulate NOD2 in response to stimuli known to promote NOD2 expression and show synergistic cytokine responses to MDP and TLR ligands previously shown to be mediated by NOD2 are informative since they may be relevant to pathogenic mechanisms leading to the spectrum of inflammation seen in Blau syndrome.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2006

Pediatric granulomatous arthritis: an international registry.

OBJECTIVE: Blau syndrome and its sporadic counterpart, early-onset sarcoidosis, share an identical phenotype featuring the classic triad of arthritis, dermatitis, and uveitis and are associated with mutations of CARD15 in 50-90% of cases. We chose the term "pediatric granulomatous arthritis" to refer to both. An international registry was established in the spring of 2005 to define the phenotype spectrum and establish the mutation frequency and variants. METHODS: Histologically confirmed granuloma and arthritis were required for inclusion. Probands and relatives were genotyped for CARD15. Deidentified clinical information was collected. RESULTS: One year after the inception of the registry, 61 individuals from 22 pedigrees had been entered. Seven pedigrees with 19 individuals (8 affected, 11 unaffected) had clinical disease that was atypical, and none of the individuals in those pedigrees showed mutations. There were 9 classic simplex pediatric granulomatous arthritis pedigrees including 19 individuals (9 affected, 10 unaffected) and 6 classic multiplex pedigrees with 22 individuals (17 affected, 5 unaffected). Cutaneous presentation was the most common. Arthritis was polyarticular in 96% of patients. Isolated eye disease was never the presenting symptom, but significant/severe visual impairment was observed in 41% of patients. Eye disease was bilateral in 21 of 22 patients and was complicated by glaucoma in 6 of 22 patients and by cataracts in 50% of patients. Skin biopsy was the best diagnostic approach (because of accuracy and low invasiveness). CONCLUSION: In this series, the first combining familial and sporadic pedigrees and, to our knowledge, the largest, we further defined the phenotype and showed that all affected classic (and no nonclassic) pedigrees carry a mutation and that there is no asymptomatic carriage. If these data are confirmed, mutation analysis rather than tissue sampling may prove to be the most efficient diagnostic procedure.

Adolescent↗
PubMed2005

A locus on chromosome 9p predisposes to a specific disease manifestation, acute anterior uveitis, in ankylosing spondylitis, a genetically complex, multisystem, inflammatory disease.

OBJECTIVE: Uveitis or intraocular inflammation is a major cause of visual loss. Acute anterior uveitis (AAU) affects approximately 40% of patients with ankylosing spondylitis (AS) but also affects patients with no evidence of spondylarthritis. We sought to determine whether a unique genetic region could be implicated in a specific manifestation-AAU-of a multisystem, inflammatory, genetically complex disease, AS. METHODS: Individuals from families multiplex for AAU were genotyped at 400 markers representing the ABI PRISM linkage map MD-10, and at the HLA-B, DRB1, DQA1, DQB1, and DPB1 alleles. Among the family members with AAU, 76 affected sibpairs were analyzed (6 without concomitant AS, 12 discordant for AS, and 58 concordant for AS). Two-point and multipoint nonparametric linkage analyses were performed, and 1-parameter allele-sharing model logarithm of odds (LOD) scores were determined. RESULTS: As previously reported for AS, linkage at the major histocompatibility complex region (chromosome 6p21) was evident, exhibiting the highest multipoint LOD score (4.96 at marker HLA-B). Strong linkage was seen at a region on chromosome 9p21-9p24, with a LOD score of 3.72 at marker D9S157. When compared with a companion cohort of AS families, the linkage at this region was found in association with AAU but not with AS. A third region on chromosome 1q23-1q31 was observed to have suggestive linkage (LOD 2.05 at marker D1S238), which overlaps with a region associated with AS. CONCLUSION: This is the first study in which a genetic region for AAU has been identified by genome-wide scan. Even though AS was highly prevalent in this cohort of families, a locus at chromosome 9p21-9p24 was identified that uniquely associates with AAU. Identifying the genetic perturbation at this region may advance our understanding of the mechanisms involved in tissue-specific pathology of complex inflammatory diseases.

Acute Disease↗
PubMed2005

Caspase recruitment domain 15 mutations and rheumatic diseases.

PURPOSE OF REVIEW: The purpose of this article is to review the foundational work and current developments on a group of rheumatic disorders associated with mutations in the caspase recruitment domain 15/nucleotide oligomerization domain 2 gene. RECENT FINDINGS: To date, there are at least 10 arthritic conditions for which specific genetic mutations have been demonstrated. They include familial Mediterranean fever; tumor necrosis factor receptor associated periodic syndrome; hyper immunoglobulin D syndrome; neonatal onset multisystemic inflammatory disease; pyogenic arthritis pyoderma gangrenosum and acne; Muckle-Wells syndrome; familial cold autoinflammatory syndrome; immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome; Crohn's disease; and familial and sporadic sarcoid granulomatous arthritis. This review focuses on recent progress in the last two diseases and the caspase recruitment domain 15 genetic defects with which they are associated. Up to 50% of patients with familial granulomatous arthritis (Blau's syndrome), 90% of those with sporadic granulomatous arthritis (early-onset sarcoidosis), and 40% of individuals with Crohn's disease have documented mutations in the caspase recruitment domain 15 gene. SUMMARY: Although histologically, Crohn's disease and familial and sporadic sarcoid granulomatous arthritis are distinct from rheumatoid arthritis because of the defining presence (albeit in not all cases) of non-caseating granulomata in the synovial and intestinal tissues, respectively, they still represent a promising model of both chronic synovitis and uveitis. In addition, once the actual mechanism is discovered by which defects of the caspase recruitment domain 15 gene product lead to chronic arthritis, it may uncover unsuspected biologic targets for therapeutics.

Caspases↗
PubMed2005

Blau syndrome mutation of CARD15/NOD2 in sporadic early onset granulomatous arthritis.

Patients with sporadic early-onset granulomatous arthritis are clinically identical to Blau syndrome, but without the family history. Blau syndrome is an autosomal dominant inherited disease and is known to be caused by mutations in the CARD15 gene (also called NOD2). We investigated the hypothesis that an individual with sporadic early onset granulomatous arthritis may have a Blau syndrome mutation in CARD15/NOD2. Our patient's genomic DNA isolated from a buccal swab sample was subjected to amplification to include the region of exon 4 from the CARD15/NOD2 gene that contains known mutations that cause Blau syndrome. This region was screened for mutations by direct DNA sequencing in both directions. One of the mutations in CARD15/NOD2 attributed to Blau syndrome was found in the DNA sample. The nucleotide change encodes an amino acid substitution from arginine to tryptophan at position 334 of the protein. This mutation has been found in some Blau syndrome pedigrees reported in the literature. These data suggest that sporadic granulomatous arthritis may in fact be the sporadic form of Blau syndrome, but arising from a spontaneous neomutation. This would explain the profound clinical identity and the lack of disease history in the parents.

Antibodies, Monoclonal↗
PubMed2004

In vivo confocal microscopy of keratic precipitates.

OBJECTIVE: To evaluate the heterogeneity of keratic precipitates (KP) in varying subtypes of uveitis by in vivo confocal microscopy (IVCM). METHODS: The KP were viewed with a scanning confocal microscope in patients (n = 33) who sought care at a tertiary referral uveitis service for immune-mediated and infectious forms of uveitis, including HLA-B27-associated uveitis, sarcoidosis, Vogt-Koyanagi-Harada syndrome, juvenile chronic arthritis, Fuchs heterochromic iridocyclitis, cytomegalovirus retinitis, herpes zoster ophthalmicus, ocular toxoplasmosis, and idiopathic uveitis. Images were captured and digitalized in real time. RESULTS: Forty-two eyes of 33 patients were examined in this study. Patient age ranged from 22 to 84 years, with a mean age of 49.4 years. Seventeen (52%) of the patients were women, and 16 patients (48%) were men. The KP ranged in diameter from 10 to 350 mum. We observed the following absolute and speculative outcomes: KP are markedly heterogeneous and variable as documented by IVCM; KP in individual patients are consistent throughout the cornea; the morphologic features of KP change across time; infectious vs noninfectious causes of uveitis seem to be readily distinguishable by using IVCM; and KP may have consistency for specific disease states and therefore may have diagnostic importance. CONCLUSIONS: To our knowledge, this is the first time that IVCM has been used to describe the architecture and heterogeneity of KP in uveitis. Such observations reveal a heterogeneity that could not be appreciated by conventional slitlamp microscopy and may have diagnostic relevance.

Adult↗
PubMed2004

Genetic studies in familial ankylosing spondylitis susceptibility.

OBJECTIVE: To define the genetic basis of susceptibility to ankylosing spondylitis (AS), especially non-major histocompatibility complex (MHC) genes. METHODS: The study group comprised 244 affected sibling pairs from 180 pedigrees of primarily European ancestry. Sibling pairs were concordant for AS by the modified New York criteria and had available sacroiliac radiographs. The subjects were genotyped for 400 markers in ABI PRISM linkage map MD-10 and for 17 additional markers on chromosomes 6p, 6q, and 11q (including HLA-B, DRB1, DQA1, DQB1, and DPB1 alleles). Two-point and multipoint nonparametric linkage (NPL) analyses were conducted using the NPL statistic and 1-parameter allele-sharing model logarithm of odds (LOD) scores, calculated using the Allele-Sharing Model (ASM) computer program. RESULTS: Linkage of the MHC region was supported by both 2-point and multipoint analyses, with the strongest peak (45.90 cM) in the MHC at the HLA-DRB1 locus (NPL score 8.720, ASM LOD score 20.49; P = 6.8 x 10(-20) for 2-point analysis). A second region was found to have positive linkage at the q arm of chromosome 6 (D6S441) in 2-point analysis; this was supported by a 39.13-cM region (135.58-174.71 cM) in multipoint analysis, with the smallest P value (4.2 x 10(-3)) at 166.39 cM. A third region was found on chromosome 11q, with the strongest evidence for linkage for D11S4094 at 123 cM (NPL score 2.235, ASM LOD score 1.939) and, on transmission disequilibrium test analysis, D11S4090 at 105.74 cM (P = 6.2 x 10(-5)). Linkage in this area was supported by multipoint analysis, spanning 22.19 cM continuously from 101.68 cM to 123.87 cM, with the strongest peak at 112.33 cM (P = 0.014); this was confirmed by subsequent fine mapping studies. CONCLUSION: Thus, this genome-wide scan implicates, in addition to the MHC, regions outside the MHC in AS susceptibility, especially on chromosomes 6q and 11q.

Chromosome Mapping↗
PubMed2003

Analysis of the ARMD1 locus: evidence that a mutation in HEMICENTIN-1 is associated with age-related macular degeneration in a large family.

Age-related macular degeneration (AMD) is a common cause of severe vision loss. Identification of the genes involved in AMD will lead to a better understanding of this disease at the molecular level, which will eventually lead to early detection, prevention and treatment. Previously, we mapped the ARMD1 gene to 1q25-31 in a large family with AMD. Here, we narrow the ARMD1 locus to 14.9 Mb between LAMB2 and D1S3469, a region containing 50 known genes. Twenty candidate genes within this region were screened for mutations. Only one DNA variation, an A16,263G transition in exon 104 of HEMICENTIN-1, was found to segregate exclusively with the disease haplotype in members of this large family with AMD. This variation produces a non-conservative substitution of arginine for glutamine at amino acid position 5345 (Gln5345Arg). It was also identified in 11 other individuals, all of whom share a haplotype, which envelops HEMICENTIN-1, with the large AMD family. The affected status of all but one of those individuals conforms to the age-dependent penetrance observed in AMD. The amino acid at position 5345 of HEMICENTIN-1 was conserved as glutamine in eight species analyzed. RT-PCR analysis demonstrated that exon 104 of HEMICENTIN-1 is alternatively spliced in various cell types. Exclusive segregation of Gln5345Arg with the disease haplotype in this large family, amino acid conservation of glutamine at this position among mammals, the non-conservative nature of the substitution and similarities to EFEMP1 support the conclusion that HEMICENTIN-1 is the ARMD1 gene.

Amino Acid Sequence↗
PubMed2003

Restoration of Ig secretion: mutation of germline-encoded residues in T15L chains leads to secretion of free light chains and assembled antibody complexes bearing secretion-impaired heavy chains.

We previously described T15H chain mutants that were impaired in assembly with L chain and in ability to be secreted from the cell. The unmutated T15L chain is unusual in that it is secretion-impaired in the absence of assembly with H chain. The T15L chain preferentially pairs with T15H in vivo, suggesting that if we introduced mutations that would allow secretion of free T15L chain, they might also lead to the secretion of the complex with the defective H chain. We mutated four positions in the germline T15L that had amino acids infrequently found in other kappa-chains. Mutation to the most frequently occurring amino acid at three of the four positions allowed secretion of free L chain, while the combination of two secretion-restoring mutations was synergistic. Coexpression of secretion-restored mutant L chains with the secretion-defective mutant H chains rescued secretion of the assembled H(2)L(2) complex, suggesting that during somatic hypermutation in vivo, deleterious mutations at the H chain may be compensated by mutations on the L chain. To our knowledge, this is the first example of mutations in IgL chains that are able to restore secretion-defective H chains to secretion competence in mammalian cells.

Amino Acid Substitution↗
PubMed2003

With a mere nod, uveitis enters a new era.

PURPOSE: To advance the knowledge of the ophthalmologist with regard to new developments in the genetics and pathologic mechanisms of uveitis. DESIGN: A review of recently published literature exploring the relationship between the nucleotide oligomerization domain (NOD2) gene and uveitis. RESULTS: Mutations in the nucleotide-binding region of NOD2 were found to be responsible for familial juvenile systemic granulomatosis (Blau syndrome or Jabs disease), a rare form of uveitis, arthritis, and dermatitis. The NOD2 gene is thought to be involved in the innate immune response to pathogens. Currently, the pathologic mechanisms behind Blau syndrome in familial juvenile systemic granulomatosis are unknown, but the interactions of NOD2 with caspases, nuclear factor kappaB, and other pathways are slowly being revealed. CONCLUSIONS: A single amino acid change in NOD2 can lead to a chronic granulomatous uveitis. By studying NOD2 and the proteins that interact with NOD2, we should gain a better understanding of the pathogenic mechanisms of uveitis and identify novel ways to halt its destructive consequences.

Carrier Proteins↗
PubMed2003

Uveitis in patients with sarcoidosis is not associated with mutations in NOD2 (CARD15).

PURPOSE: Mutations in NOD2 are responsible for Blau syndrome, a systemic disease triad involving the uvea, joints, and skin. NOD2 mutations are also associated with Crohn disease. Both Blau syndrome and Crohn disease involve granulomatous inflammation and uveitis, as does sarcoidosis. We sought to determine if NOD2 mutations were present in patients with sarcoidosis, especially those with uveitis. METHODS: NOD2 gene exons were sequenced from DNA obtained from sarcoidosis patients. The diagnoses of sarcoidosis and uveitis were verified from clinical records. RESULTS: NOD2 polymorphisms were found in 26 patients with sarcoidosis (13 with uveitis). There was no significant difference in allele frequencies between patients with and without uveitis. CONCLUSIONS: Despite the strikingly similar pathologies of Blau syndrome and sarcoidosis, no mutations were found to be associated with sarcoidosis in a group of patients, regardless of the presence of uveitis.

Adult↗
PubMed2003

Genetics of uveitis.

Uveitis phenotypes can differ substantially, and most uveitis diseases are considered polygenic with complex inheritance patterns. When considering the genetics of these diseases, common threads can be identified. For example, in virtually every polygenic disease studied, there exists an HLA genetic association. This association can be strong, such as the associations of HLA-B27 with AAU and HLA-A29 with BSCR; or it can be more subtle, involving several HLA genes or a combination of HLA genes that compose specific haplotypes. In many of these conditions, it is hypothesized that genes other than classic MHC genes but located at the MHC locus may be important susceptibility genes. Genome-wide scans and other genetic methods are becoming increasingly successful in identifying genetic loci and candidate genes in many inflammatory disorders that have an uveitic component. It will be important to test these findings as uveitis-specific genetic factors. Therefore, the burgeoning understanding of the human genome promises to result in new insight into the pathogenesis of uveitis.

Humans↗
PubMed2003

HLA-B27-associated uveitis: overview and current perspectives.

PURPOSE OF REVIEW: To review current knowledge about the pathogenesis, clinical presentation, and treatment of HLA-B27-associated uveitis, which is the most commonly identified cause of uveitis in community-based practice and an important cause of ocular morbidity. RECENT FINDINGS: Significant advances have been made in understanding the pathogenesis of HLA-B27-associated ocular and systemic disease, especially with regard to the genetic underpinning of these diseases. Increasing attention has also been focused on the use of alternative therapies in the treatment of HLA-B27-associated uveitis, with special attention to sulfa class antibiotics, historically have been used to treat the articular manifestations of the spondyloarthritides, and newer drugs that inhibit tumor necrosis factor-alpha. SUMMARY: The next several years promise to yield exciting new advances in understanding of the genetic epidemiology and treatment of HLA-B27-associated uveitis.

Adrenal Cortex Hormones↗
PubMed2003

Strong associations between specific HLA-DQ and HLA-DR alleles and the tubulointerstitial nephritis and uveitis syndrome.

PURPOSE: To identify genetic markers for the tubulointerstitial nephritis and uveitis (TINU) syndrome by using human leukocyte antigen (HLA) genotyping. METHODS: Eighteen patients who had TINU syndrome were evaluated at three institutions. Typing of class I and II genes was performed by using DNA-based techniques. RESULTS: Significant associations were found with HLA-B14 (6/18 patients, 33.3%; control subjects, 5.5%; P = 0.0003; relative risk [RR] = 8.5), HLA-DQA1*01 (17/18 patients, 94.4%; control subjects, 46.6%, P = 0.0001; RR = 19.5), HLA-DQA1*0101 (14/18 patients, 77.8%; control subjects 22.2%; P < 0.0001; RR = 12.2), HLA-DQB1*05 (14/18 patients, 77.8%; control subjects 17.7%; P < 0.0001; RR = 16.3), HLA-DQB1*0501 (13/18 patients, 72.2%; control subjects 12.9%; P < 0.0001; RR = 17.6), HLA-DRB1*01 (14/18 patients, 77.8%; control subjects, 12.1%; P < 0.0001; RR = 25.5), and HLA-DRB1*0102 (13/18 patients, 72.2%; control subjects, 1.6%; P < 0.0001, RR = 167.1). The HLA haplotype most frequently identified in the study patients was HLA-DQA1*01/DQB1*05/DRB1*01 (13/18 patients, 72.2%). CONCLUSIONS: TINU syndrome is strongly associated with HLA-DQA1*01, HLA-DQB1*05, and HLA-DRB1*01. The association with HLA-DRB1*0102 is one of the highest reported for any disease. Because these genes are in linkage disequilibrium, the role of the individual alleles is difficult to assess. Based on the results of the present study and on previously reported HLA associations in patients with TINU syndrome, the alphabeta dimer encoded by HLA-DQA1*01/DQB1*05 may be particularly important in conferring risk for development of this disease.

Adolescent↗
PubMed2003

Immunohistology of antigen-presenting cells in vivo: a novel method for serial observation of fluorescently labeled cells.

PURPOSE: Dendritic cells and macrophages are phagocytic antigen-presenting cells that bridge the innate and acquired immune systems. The coexistence of subtypes of dendritic cells and macrophages with overlapping properties complicates resolution of their precise roles in an immune response within a given tissue. This report documents a method to identify and observe these cells over time in a living animal and thereby to visualize them during a dynamic immune response. METHODS: To label potential antigen-presenting cells, fluorescently tagged ovalbumin was injected into the anterior chambers of mouse eyes. Fluorescently tagged antibodies to cell surface proteins were injected to label specific cell types. Intravital fluorescence microscopy with digital image recording was used to visualize the labeled cells in the irises at various times after the injection. RESULTS: The pattern and density (116-148 cells/mm(2)) of cells labeled in vivo by fluorescent ovalbumin or F4/80 antibodies were similar to that identified by conventional wholemount immunostaining for macrophages and dendritic cells. Fluorescent antibodies specific for CD11b, CD11c, CD80, CD86, or major histocompatibility complex (MHC) class II protein each labeled selective populations of cells in vivo. In contrast to conventional histology, in vivo immunohistology permitted serial observations. The phenotype of cells labeled by fluorescent ovalbumin was not the same at 6 (95% CD11c(+)) and 24 hours (24% CD11c(+)) after injection. CONCLUSIONS: This method of in vivo immunohistology provides a tool for studying cell kinetics and dynamic interactions that cannot be assessed by conventional immunohistology. Furthermore, it avoids potential artifacts from tissue fixation and may work with antibodies that label cells poorly in vitro.

Animals↗
PubMed2002

Immune mechanisms in uveitis. What can be learned from in vivo imaging?

In many aspects, in vivo imaging is superior to other techniques, such as conventional histology, because it allows the stepwise process of leukocyte migration to be dissected. The potential uses of the in vivo imaging techniques have yet to be achieved. The transfer of lymphocytes with fluorescent dyes can be marked. APCs that ingest fluorescent antigen and use fluorescent antibodies specifically to label different types of APCs in the anterior segment can be identified. Combining these techniques could result in more exciting insights into uveitis and the mechanisms of the immune system. For example, one can confidently expect to be able to observe the extravasation of CFSE-marked DO11.10 T cells and their subsequent interaction with APCs containing red fluorescent OVA. The use of green fluorescent protein to measure the expression of various proteins has occurred in a variety of in vitro and in vivo models. To identify activated T cells specifically, heterozygous knock-in mice have been generated that have a cDNA for enhanced green fluorescent protein substituted for the IL-2 coding region on one allele [91]. Activated T cells from these IL-2-green fluorescent protein mice up-regulate the expression of the IL-2 gene and consequently synthesize the green fluorescent protein marker. The authors recently demonstrated the presence of these activated cells in vivo in the mouse iris [16]. With both the green fluorescent protein and the brighter yellow fluorescent protein the authors anticipate being able to detect in vivo the expression of various cytokines, such as IL-2, the Th1 cytokine IFN-gamma, or the Th2 cytokine IL-4, in T cells infiltrating the eye. First steps have been undertaken to establish in vivo imaging in human eyes. Toxicity of fluorescent dyes currently used for animal research and movement artifacts of the tissue under investigation amplified by the high magnification necessary for cell research, however, remain the major challenges to study leukocyte migration in human uveitis.

Antigen-Presenting Cells↗