ABSTRACT Anti-neutrophil cytoplasmic antibodies (ANCA) are antibodies directed against enzymes th... more ABSTRACT Anti-neutrophil cytoplasmic antibodies (ANCA) are antibodies directed against enzymes that are found mainly within the azurophil or primary granules of neutrophils. There are 3 types of ANCA that can be distinguished by the patterns they produce by indirect immunofluorescence when tested on normal ethanol-fixed neutrophils. Diffuse fine granular cytoplasmic fluorescence (cANCA) is typically found in Wegener's granulomatosis, in some cases of microscopic polyarteritis and Churg Strauss syndrome, and in some cases of crescentic and segmental necrotising glomerulonephritis, but it is rare in other conditions. The target antigen is usually proteinase 3. Perinuclear fluorescence (pANCA) is found in many cases of microscopic polyarteritis and in other cases of crescentic and segmental necrotising glomerulonephritis. These antibodies are often directed against myeloperoxidase but other targets include elastase, cathepsin G, lactoferrin, lysozyme and beta-glucuronidase. The third group designated "atypical" ANCA includes neutrophil nuclear fluorescence and some unusual cytoplasmic patterns, and while a few of the target antigens are shared with pANCA, the others have not been identified. Sera that produce a pANCA or atypical ANCA pattern on alcohol-fixed neutrophils result in cytoplasmic fluorescence when formalin acetone fixation is used. pANCA or atypical ANCA occur in about 2/3 of all individuals with ulcerative colitis or primary sclerosing cholangitis, and they are found in a third of patients with Crohn's disease. The reported incidence of ANCA in rheumatoid arthritis and SLE varies considerably but the patterns are predominantly pANCA and atypical ANCA.(ABSTRACT TRUNCATED AT 250 WORDS)
Jessica Metcalfe, Nina D, Vaz, Maria Makrides, Michael S.Gold, Patrick Quinn, Richard Loh, Susan ... more Jessica Metcalfe, Nina D, Vaz, Maria Makrides, Michael S.Gold, Patrick Quinn, Richard Loh, Susan L. Prescott, Debra J.Palmer
Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought t... more Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune diseases, while the contribution of rare variants remains unclear. Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls. We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK1, which are present alone, or in combination, in a substantial proportion of lupus patients. The rare variants found in patients, but not those found exclusively in controls, impair suppression of IRF5 and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice. Thus, rare gene variants are common in SLE and likely contribute to genetic risk.
Lepidopterism is a general term for the ill-effects to humans from contact with moths and butterf... more Lepidopterism is a general term for the ill-effects to humans from contact with moths and butterflies. We describe two cases of systemic reactions after contact with the cocoon of the Australian species Chelepteryx collesi, or white-stemmed gum moth-irritant and toxic effects in one and a systemic allergic reaction in the other. Early removal of urticating hairs from the skin in such cases may be advisable.
Objective: Granulomatous polyangiitis patients generally have ANCA targeting Proteinase 3 (PR3), ... more Objective: Granulomatous polyangiitis patients generally have ANCA targeting Proteinase 3 (PR3), while microscopic polyangiitis and eosinophilic granulomatous polyangiitis patients generally have ANCA targeting myeloperoxidase (MPO). Patients positive for both PR3-ANCA and MPO-ANCA are uncommon and any diagnostic value of this situation has not been well described. The aim of this study was to determine whether there were any patterns of clinical presentations or outcomes of patients who tested positive for both PR3-ANCA and MPO-ANCA. Methods: A retrospective clinical audit was carried out. A list of patients who had tested positive for both PR3-ANCA and MPO-ANCA was obtained from ACT Pathology from 2003-2013. Medical records were then used to determine their clinical outcomes. Results: 3 of the 15 study patients were found to have ANCA-associated vasculitis (AAV), two with MPA and the other EGPA along with a non-AAV autoimmune disease. 1 patient had drug-induced vasculitis and 4 had a non-AAV autoimmune disease. An additional three patients had a non-AVV autoimmune disease, but one concurrently had a malignancy while the other two had recurrent infections. Two patients had a malignancy, another one only had recurrent infections, and the remaining patient was lost to follow up with an undiagnosed inflammatory condition. Conclusion: Pathology results showing dual positivity for PR3-ANCA and MPO-ANCA in itself does not appear to indicate any particular pattern of clinical outcome and so cannot be used to draw any clinical conclusions at the time of presentation. The 3 cases of AAV demonstrated MPO-predominance which fitted with their final diagnosis.
aimed at human immunology. This was particularly disappointing when there are a number of well de... more aimed at human immunology. This was particularly disappointing when there are a number of well described separation techniques that are available for human systems and are close to being of clinical value in the dissection of immune abnormalities in patients. Conventional lymphocyte activation was well but again uncritically described, in contrast to the chapters on cytokines which were dated and disappointing. Delayed type hypersensitivity was covered well but to do so without reference to the widely used Multitest is unfortunate. All in all this book is sometimes a useful set of laboratory instructions,
Recurrent spontaneous abortion (RSA) is a common complication of pregnancy for which there is no ... more Recurrent spontaneous abortion (RSA) is a common complication of pregnancy for which there is no known cure. Therefore, effective treatment is needed. Published results from controlled clinical trials of allogeneic leukocyte immunization of women suffering from RSA have given conflicting results. To address this controversy, the international raw data of all patients who had been entered into clinical trials that included a control group were collected and analyzed. The primary question to be answered was whether alloimmune stimulation of the female partner improves the subsequent live birth rate. Fifteen clinical centers were identified worldwide because they controlled appropriate raw data. Consequently, nine randomized trials (seven double-blinded) were evaluated independently by two separate data analysis teams to assure conclusions were robust. One team also compared randomized trials to the results of six nonrandomized cohort-controlled studies to test for bias in nonrandomized trials. Factors predicting successful live births among couples with RSA were evaluated by logistic regression. Although the two independent analyses made use of different definitions and utilized different statistical methods, the results of both were similar. The live births ratios (ratio of live births in treatment and control groups) with 95% confidence intervals (CI) were 1.16 (CI, 1.01-1.34, P = 0.031) and 1.21 (CI, 1.04-1.37, P = 0.024), respectively. The absolute differences in live birth rates between treatment and control groups were 8% and 10% in respective analyses. Results in randomized and nonrandomized trials were surprisingly similar despite significant differences in composition of control and treatment groups. Live birth rates were lower with older female partners, more than five abortions, with a positive ANA or with positive anticardiolipin antibodies. Live birth rates were higher if the female partner had prior to treatment serum antibodies to paternal leukocytes or converted from negative to positive with immunization. Approximately 0.5% of controls and 2.1% of treated patients experience side effects for a 1.6% treatment related effect. There was no evidence of an increased risk of adverse effects on the fetus. Two independent analyses of worldwide data on allogeneic leukocyte immunization for treatment of RSA suggest that alloimmunization may be an effective treatment The treatment effect appears, however, to be small, and the data indicate that immunotherapy helps only 8% to 10% of affected couples. A current lack of diagnostic tests defining patients who most likely would benefit from immunotherapy, precludes the identification of a patient population that would benefit most from such treatment. The efficacy of treatment in such a subgroup could be expected to increase and could be of sufficient magnitude to allow the determination of more effective immunization protocols. This study does not exclude the possibility of a partial correction of a widely prevalent immunology defect by immunotherapy. The presence of such a defect would indicate a need for more effective therapy. The unexplained variation in pregnancy success rates of control groups among centers continues to present a statistical problem, limiting the statistical evaluation of retroactively obtained data.
Abstract of poster that presented at the Australasian Society of Clinical Immunology and Allergy ... more Abstract of poster that presented at the Australasian Society of Clinical Immunology and Allergy (ASCIA) 24th Annual Scientific Meeting, 11-13 September 2013, Perth, Australia
Objectives ANCA-associated vasculitis (AAV) can affect all age groups. We aimed to show that diff... more Objectives ANCA-associated vasculitis (AAV) can affect all age groups. We aimed to show that differences in disease presentation and 6 month outcome between younger- and older-onset patients are still incompletely understood. Methods We included patients enrolled in the Diagnostic and Classification Criteria for Primary Systemic Vasculitis (DCVAS) study between October 2010 and January 2017 with a diagnosis of AAV. We divided the population according to age at diagnosis: <65 years or ≥65 years. We adjusted associations for the type of AAV and the type of ANCA (anti-MPO, anti-PR3 or negative). Results A total of 1338 patients with AAV were included: 66% had disease onset at <65 years of age [female 50%; mean age 48.4 years (s.d. 12.6)] and 34% had disease onset at ≥65 years [female 54%; mean age 73.6 years (s.d. 6)]. ANCA (MPO) positivity was more frequent in the older group (48% vs 27%; P = 0.001). Younger patients had higher rates of musculoskeletal, cutaneous and ENT manifes...
The review seeks to summarise the current ideas in regard to the pathogenesis of ANCA-associated ... more The review seeks to summarise the current ideas in regard to the pathogenesis of ANCA-associated vasculitis and to examine in detail how epidemiological and genetic factors fit with the modern paradigm. The recent literature has been reviewed. The AASV appear to involve initiation by both T cells and B cells followed by a neutrophil dominated inflammatory phase in which ANCA may actually be involved. The alternative complement pathway may play a role. The genetic background is reviewed with genes identified that potentially encode proteins that are involved in the regulation of the immune system, other genes may be involved in the control of the inflammatory phase. With regard to environmental factors the two that stand out are a latitude gradient, presumably vitamin D and silica an agent known to be associated with both autoantibody production and autoimmune disease. A model which includes these factors is outlined.
Journal of immunology (Baltimore, Md. : 1950), 1982
The helper/inducer (Leu-3) and suppressor/cytotoxic (Leu-2) sublineages of human peripheral blood... more The helper/inducer (Leu-3) and suppressor/cytotoxic (Leu-2) sublineages of human peripheral blood T cells can both the subdivided into functionally distinct subsets with anti-Leu-8, a new monoclonal antibody that identifies 75 +/- 10% of the Leu-3 cells and 60 +/- 10% of the Leu-2 cells. Using the autologous MLR as a T cell-dependent stimulus for immunoglobulin synthesis, we have shown that the major helper effect for antibody formation lies within the numerically minor Leu-3,8- subset. In addition, neither Leu-2,8- cells alone suppress Leu-3-induced immunoglobulin synthesis, but in combination these subsets are markedly inhibitory. These results indicate that at least two phenotypically distinct cell types of suppressor lineage interact to produce suppression of an immune response in man.
ABSTRACT Anti-neutrophil cytoplasmic antibodies (ANCA) are antibodies directed against enzymes th... more ABSTRACT Anti-neutrophil cytoplasmic antibodies (ANCA) are antibodies directed against enzymes that are found mainly within the azurophil or primary granules of neutrophils. There are 3 types of ANCA that can be distinguished by the patterns they produce by indirect immunofluorescence when tested on normal ethanol-fixed neutrophils. Diffuse fine granular cytoplasmic fluorescence (cANCA) is typically found in Wegener&#39;s granulomatosis, in some cases of microscopic polyarteritis and Churg Strauss syndrome, and in some cases of crescentic and segmental necrotising glomerulonephritis, but it is rare in other conditions. The target antigen is usually proteinase 3. Perinuclear fluorescence (pANCA) is found in many cases of microscopic polyarteritis and in other cases of crescentic and segmental necrotising glomerulonephritis. These antibodies are often directed against myeloperoxidase but other targets include elastase, cathepsin G, lactoferrin, lysozyme and beta-glucuronidase. The third group designated &quot;atypical&quot; ANCA includes neutrophil nuclear fluorescence and some unusual cytoplasmic patterns, and while a few of the target antigens are shared with pANCA, the others have not been identified. Sera that produce a pANCA or atypical ANCA pattern on alcohol-fixed neutrophils result in cytoplasmic fluorescence when formalin acetone fixation is used. pANCA or atypical ANCA occur in about 2/3 of all individuals with ulcerative colitis or primary sclerosing cholangitis, and they are found in a third of patients with Crohn&#39;s disease. The reported incidence of ANCA in rheumatoid arthritis and SLE varies considerably but the patterns are predominantly pANCA and atypical ANCA.(ABSTRACT TRUNCATED AT 250 WORDS)
Jessica Metcalfe, Nina D, Vaz, Maria Makrides, Michael S.Gold, Patrick Quinn, Richard Loh, Susan ... more Jessica Metcalfe, Nina D, Vaz, Maria Makrides, Michael S.Gold, Patrick Quinn, Richard Loh, Susan L. Prescott, Debra J.Palmer
Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought t... more Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune diseases, while the contribution of rare variants remains unclear. Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls. We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK1, which are present alone, or in combination, in a substantial proportion of lupus patients. The rare variants found in patients, but not those found exclusively in controls, impair suppression of IRF5 and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice. Thus, rare gene variants are common in SLE and likely contribute to genetic risk.
Lepidopterism is a general term for the ill-effects to humans from contact with moths and butterf... more Lepidopterism is a general term for the ill-effects to humans from contact with moths and butterflies. We describe two cases of systemic reactions after contact with the cocoon of the Australian species Chelepteryx collesi, or white-stemmed gum moth-irritant and toxic effects in one and a systemic allergic reaction in the other. Early removal of urticating hairs from the skin in such cases may be advisable.
Objective: Granulomatous polyangiitis patients generally have ANCA targeting Proteinase 3 (PR3), ... more Objective: Granulomatous polyangiitis patients generally have ANCA targeting Proteinase 3 (PR3), while microscopic polyangiitis and eosinophilic granulomatous polyangiitis patients generally have ANCA targeting myeloperoxidase (MPO). Patients positive for both PR3-ANCA and MPO-ANCA are uncommon and any diagnostic value of this situation has not been well described. The aim of this study was to determine whether there were any patterns of clinical presentations or outcomes of patients who tested positive for both PR3-ANCA and MPO-ANCA. Methods: A retrospective clinical audit was carried out. A list of patients who had tested positive for both PR3-ANCA and MPO-ANCA was obtained from ACT Pathology from 2003-2013. Medical records were then used to determine their clinical outcomes. Results: 3 of the 15 study patients were found to have ANCA-associated vasculitis (AAV), two with MPA and the other EGPA along with a non-AAV autoimmune disease. 1 patient had drug-induced vasculitis and 4 had a non-AAV autoimmune disease. An additional three patients had a non-AVV autoimmune disease, but one concurrently had a malignancy while the other two had recurrent infections. Two patients had a malignancy, another one only had recurrent infections, and the remaining patient was lost to follow up with an undiagnosed inflammatory condition. Conclusion: Pathology results showing dual positivity for PR3-ANCA and MPO-ANCA in itself does not appear to indicate any particular pattern of clinical outcome and so cannot be used to draw any clinical conclusions at the time of presentation. The 3 cases of AAV demonstrated MPO-predominance which fitted with their final diagnosis.
aimed at human immunology. This was particularly disappointing when there are a number of well de... more aimed at human immunology. This was particularly disappointing when there are a number of well described separation techniques that are available for human systems and are close to being of clinical value in the dissection of immune abnormalities in patients. Conventional lymphocyte activation was well but again uncritically described, in contrast to the chapters on cytokines which were dated and disappointing. Delayed type hypersensitivity was covered well but to do so without reference to the widely used Multitest is unfortunate. All in all this book is sometimes a useful set of laboratory instructions,
Recurrent spontaneous abortion (RSA) is a common complication of pregnancy for which there is no ... more Recurrent spontaneous abortion (RSA) is a common complication of pregnancy for which there is no known cure. Therefore, effective treatment is needed. Published results from controlled clinical trials of allogeneic leukocyte immunization of women suffering from RSA have given conflicting results. To address this controversy, the international raw data of all patients who had been entered into clinical trials that included a control group were collected and analyzed. The primary question to be answered was whether alloimmune stimulation of the female partner improves the subsequent live birth rate. Fifteen clinical centers were identified worldwide because they controlled appropriate raw data. Consequently, nine randomized trials (seven double-blinded) were evaluated independently by two separate data analysis teams to assure conclusions were robust. One team also compared randomized trials to the results of six nonrandomized cohort-controlled studies to test for bias in nonrandomized trials. Factors predicting successful live births among couples with RSA were evaluated by logistic regression. Although the two independent analyses made use of different definitions and utilized different statistical methods, the results of both were similar. The live births ratios (ratio of live births in treatment and control groups) with 95% confidence intervals (CI) were 1.16 (CI, 1.01-1.34, P = 0.031) and 1.21 (CI, 1.04-1.37, P = 0.024), respectively. The absolute differences in live birth rates between treatment and control groups were 8% and 10% in respective analyses. Results in randomized and nonrandomized trials were surprisingly similar despite significant differences in composition of control and treatment groups. Live birth rates were lower with older female partners, more than five abortions, with a positive ANA or with positive anticardiolipin antibodies. Live birth rates were higher if the female partner had prior to treatment serum antibodies to paternal leukocytes or converted from negative to positive with immunization. Approximately 0.5% of controls and 2.1% of treated patients experience side effects for a 1.6% treatment related effect. There was no evidence of an increased risk of adverse effects on the fetus. Two independent analyses of worldwide data on allogeneic leukocyte immunization for treatment of RSA suggest that alloimmunization may be an effective treatment The treatment effect appears, however, to be small, and the data indicate that immunotherapy helps only 8% to 10% of affected couples. A current lack of diagnostic tests defining patients who most likely would benefit from immunotherapy, precludes the identification of a patient population that would benefit most from such treatment. The efficacy of treatment in such a subgroup could be expected to increase and could be of sufficient magnitude to allow the determination of more effective immunization protocols. This study does not exclude the possibility of a partial correction of a widely prevalent immunology defect by immunotherapy. The presence of such a defect would indicate a need for more effective therapy. The unexplained variation in pregnancy success rates of control groups among centers continues to present a statistical problem, limiting the statistical evaluation of retroactively obtained data.
Abstract of poster that presented at the Australasian Society of Clinical Immunology and Allergy ... more Abstract of poster that presented at the Australasian Society of Clinical Immunology and Allergy (ASCIA) 24th Annual Scientific Meeting, 11-13 September 2013, Perth, Australia
Objectives ANCA-associated vasculitis (AAV) can affect all age groups. We aimed to show that diff... more Objectives ANCA-associated vasculitis (AAV) can affect all age groups. We aimed to show that differences in disease presentation and 6 month outcome between younger- and older-onset patients are still incompletely understood. Methods We included patients enrolled in the Diagnostic and Classification Criteria for Primary Systemic Vasculitis (DCVAS) study between October 2010 and January 2017 with a diagnosis of AAV. We divided the population according to age at diagnosis: <65 years or ≥65 years. We adjusted associations for the type of AAV and the type of ANCA (anti-MPO, anti-PR3 or negative). Results A total of 1338 patients with AAV were included: 66% had disease onset at <65 years of age [female 50%; mean age 48.4 years (s.d. 12.6)] and 34% had disease onset at ≥65 years [female 54%; mean age 73.6 years (s.d. 6)]. ANCA (MPO) positivity was more frequent in the older group (48% vs 27%; P = 0.001). Younger patients had higher rates of musculoskeletal, cutaneous and ENT manifes...
The review seeks to summarise the current ideas in regard to the pathogenesis of ANCA-associated ... more The review seeks to summarise the current ideas in regard to the pathogenesis of ANCA-associated vasculitis and to examine in detail how epidemiological and genetic factors fit with the modern paradigm. The recent literature has been reviewed. The AASV appear to involve initiation by both T cells and B cells followed by a neutrophil dominated inflammatory phase in which ANCA may actually be involved. The alternative complement pathway may play a role. The genetic background is reviewed with genes identified that potentially encode proteins that are involved in the regulation of the immune system, other genes may be involved in the control of the inflammatory phase. With regard to environmental factors the two that stand out are a latitude gradient, presumably vitamin D and silica an agent known to be associated with both autoantibody production and autoimmune disease. A model which includes these factors is outlined.
Journal of immunology (Baltimore, Md. : 1950), 1982
The helper/inducer (Leu-3) and suppressor/cytotoxic (Leu-2) sublineages of human peripheral blood... more The helper/inducer (Leu-3) and suppressor/cytotoxic (Leu-2) sublineages of human peripheral blood T cells can both the subdivided into functionally distinct subsets with anti-Leu-8, a new monoclonal antibody that identifies 75 +/- 10% of the Leu-3 cells and 60 +/- 10% of the Leu-2 cells. Using the autologous MLR as a T cell-dependent stimulus for immunoglobulin synthesis, we have shown that the major helper effect for antibody formation lies within the numerically minor Leu-3,8- subset. In addition, neither Leu-2,8- cells alone suppress Leu-3-induced immunoglobulin synthesis, but in combination these subsets are markedly inhibitory. These results indicate that at least two phenotypically distinct cell types of suppressor lineage interact to produce suppression of an immune response in man.
Uploads
Papers by Paul Gatenby