Publications by authors named "Cory Perugino"

33 Publications

Vaccine serologic responses among transplant patients associate with COVID-19 infection and T peripheral helper cells.

medRxiv 2021 Jul 14. Epub 2021 Jul 14.

Background: Therapeutically immunosuppressed transplant recipients exhibit attenuated responses to COVID-19 vaccines. To better understand the immune alterations that determined poor vaccine response, we correlated quantities of circulating T and B cell subsets at baseline with longitudinal serologic responses to SARS-CoV-2 mRNA vaccination in heart and lung transplant recipients.

Methods: Samples at baseline and at approximately 8 and 30 days after each vaccine dose for 22 heart and lung transplant recipients with no history of COVID-19, four heart and lung transplant recipients with prior COVID-19 infection, and 12 healthy controls undergoing vaccination were analyzed. Anti-spike protein receptor binding domain (RBD) IgG and pseudovirus neutralization activity were measured. Proportions of B and T cell subsets at baseline were comprehensively quantitated.

Results: At 8-30 days post vaccination, healthy controls displayed robust anti-RBD IgG responses, whereas heart and lung transplant recipients showed minimally increased responses. A parallel absence of activity was observed in pseudovirus neutralization. In contrast, three of four (75%) transplant recipients with prior COVID-19 infection displayed robust responses at levels comparable to controls. Baseline levels of activated PD-1 HLA-DR CXCR5 CD4 T cells (also known as T peripheral helper [T ] cells) and CD4+ T cells strongly predicted the ability to mount a response.

Conclusions: Immunosuppressed patients have defective vaccine responses but can be induced to generate neutralizing antibodies after SARS-CoV-2 infection. Strong correlations of vaccine responsiveness with baseline T and CD4 T cell numbers highlights a role for T helper activity in B cell differentiation into antibody secreting cells during vaccine response.
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http://dx.doi.org/10.1101/2021.07.11.21260338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288159PMC
July 2021

Neutralizing anti-IL-1 receptor antagonist autoantibodies induce inflammatory and fibrotic mediators in IgG4-related disease.

J Allergy Clin Immunol 2021 May 8. Epub 2021 May 8.

Department of Medicine, Division of Immunology and Rheumatology, Stanford University, Stanford, Calif; Institute for Immunity, Transplant and Infection, Stanford University, Stanford, Calif; VA Palo Alto Health Care System, Palo Alto, Calif. Electronic address:

Background: IgG4-related disease (IgG4-RD) is a fibroinflammatory condition involving loss of B-cell tolerance and production of autoantibodies. However, the relevant targets and role of these aberrant humoral immune responses are not defined.

Objective: Our aim was to identify novel autoantibodies and autoantigen targets that promote pathogenic responses in IgG4-RD.

Methods: We sequenced plasmablast antibody repertoires in patients with IgG4-RD. Representative mAbs were expressed and their specificities characterized by using cytokine microarrays. The role of anti-IL-1 receptor antagonist (IL-1RA) autoantibodies was investigated by using in vitro assays.

Results: We identified strong reactivity against human IL-1RA by using a clonally expanded plasmablast-derived mAb from a patient with IgG4-RD. Plasma from patients with IgG4-RD exhibited elevated levels of reactivity against IL-1RA compared with plasma from the controls and neutralized IL-1RA activity, resulting in inflammatory and fibrotic mediator production in vitro. IL-1RA was detected in lesional tissues from patients with IgG4-RD. Patients with anti-IL-1RA autoantibodies of the IgG4 subclass had greater numbers of organs affected than did those without anti-IL-1RA autoantibodies. Peptide analyses identified IL-1RA epitopes targeted by anti-IL-1RA antibodies at sites near the IL-1RA/IL-1R interface. Serum from patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) also had elevated levels of anti-IL-1RA autoantibodies compared with those of the controls.

Conclusion: A subset of patients with IgG4-RD have anti-IL-1RA autoantibodies, which promote proinflammatory and profibrotic meditator production via IL-1RA neutralization. These findings support a novel immunologic mechanism underlying the pathogenesis of IgG4-RD. Anti-IL-1RA autoantibodies are also present in a subset of patients with SLE and RA, suggesting a potential common pathway in multiple autoimmune diseases.
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http://dx.doi.org/10.1016/j.jaci.2021.05.002DOI Listing
May 2021

Expansion of Cytotoxic CD4+ T cells in the lungs in severe COVID-19.

medRxiv 2021 Mar 26. Epub 2021 Mar 26.

The contributions of T cells infiltrating the lungs to SARS-CoV-2 clearance and disease progression are poorly understood. Although studies of CD8+ T cells in bronchoalveolar lavage and blood have suggested that these cells are exhausted in severe COVID-19, CD4+ T cells have not been systematically interrogated within the lung parenchyma. We establish here that cytotoxic CD4+ T cells (CD4+CTLs) are prominently expanded in the COVID-19 lung infiltrate. CD4+CTL numbers in the lung increase with disease severity and progression is accompanied by widespread HLA-DR expression on lung epithelial and endothelial cells, increased apoptosis of epithelial cells and tissue remodeling. Based on quantitative evidence for re-activation in the lung milieu, CD4+ CTLs are as likely to drive viral clearance as CD8+ T cells and may also be contributors to lung inflammation and eventually to fibrosis in severe COVID-19.

In Brief: In severe COVID-19 cytotoxic CD4+ T cells accumulate in draining lymph nodes and in the lungs during the resolving phase of the disease. Re-activated cytotoxic CD4+ T cells and cytotoxic CD8+ T cells are present in roughly equivalent numbers in the lungs at this stage and these cells likely collaborate to eliminate virally infected cells and potentially induce fibrosis. A large fraction of epithelial and endothelial cells in the lung express HLA class II in COVID-19 and there is temporal convergence between CD4+CTL accumulation and apoptosis in the lung.

Highlights: In severe COVID-19, activated CD4+ CTLs accumulate in the lungs late in diseaseThese cells likely participate in SARS-CoV-2 clearance, collaborating with CD8+ T cells many of which exhibit an exhausted phenotypeT cells likely contribute to the late exacerbation of inflammationCD4+CTLs have been linked to fibrosis in many disorders and could also be responsible for the eventual induction of fibrosis in a subset of COVID-19 patients.

Summary: The contributions of T cells infiltrating the lungs to SARS-CoV-2 clearance and disease progression are poorly understood. Although studies of CD8+ T cells in bronchoalveolar lavage and blood have suggested that these cells are exhausted in severe COVID-19, CD4+ T cells have not been systematically interrogated within the lung parenchyma. We establish here that cytotoxic CD4+ T cells (CD4+CTLs) are prominently expanded in the COVID-19 lung infiltrate. CD4+CTL numbers in the lung increase with disease severity and progression is accompanied by widespread HLA-DR expression on lung epithelial and endothelial cells, increased apoptosis of epithelial cells and tissue remodeling. Based on quantitative evidence for re-activation in the lung milieu, CD4+ CTLs are as likely to drive viral clearance as CD8+ T cells and may also be contributors to lung inflammation and eventually to fibrosis in severe COVID-19.
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http://dx.doi.org/10.1101/2021.03.23.21253885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010762PMC
March 2021

The Association of Smoking with IgG4-Related Disease: A Case-Control Study.

Rheumatology (Oxford) 2021 Mar 5. Epub 2021 Mar 5.

Rheumatology Unit, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, MA.

Objective: To evaluate the association between cigarette smoking and the odds of IgG4-related disease (IgG4-RD).

Methods: We performed a case-control study of patients with IgG4-RD, compared in a 1:5 ratio with age-, race- and sex-matched controls. We included cases evaluated at Massachusetts General Hospital, a hospital within the Mass General Brigham (MGB) System. Controls were identified from the MGB Biobank. Smoking status at date of IgG4-RD diagnosis or corresponding index date was determined. Conditional logistic regression was used to estimate the association between cigarette smoking and odds of having IgG4-RD.

Results: There were 234 IgG4-RD cases and 1,170 controls. Mean age (59 years), sex (62% male), and race (75% white) were well-balanced. IgG4-RD cases were more likely to be current smokers compared with controls (25 [11%] vs 70 [6%], OR 1.79 [95% CI 1.08-2.95]). This association was strongest among female cases (13 [14%] vs 19 [4%], OR 3.79 [95% CI 1.71-8.39]) and those with retroperitoneal fibrosis (RPF, 13 [28%] vs 13 [6%], OR 6.93 [95% CI 2.78-17.26]) or normal IgG4 concentrations (21 [21%] vs 21 [4%], OR 6.22 [95% CI 3.09-12.49]). When RPF cases were excluded, there was no longer an association between current smoking and the odds of having IgG4-RD (12 [6%] vs 57 [6%], OR 0.95 [95% CI 0.49-1.86]).

Conclusion: Being a current smoker is associated with greater odds of having IgG4-RD, especially among women and those with RPF or normal IgG4 concentrations. Current smoking is the first recognized modifiable risk factor for IgG4-RD.
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http://dx.doi.org/10.1093/rheumatology/keab172DOI Listing
March 2021

Congruent microbiome signatures in fibrosis-prone autoimmune diseases: IgG4-related disease and systemic sclerosis.

Genome Med 2021 Feb 28;13(1):35. Epub 2021 Feb 28.

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Background: Immunoglobulin G4-related disease (IgG4-RD) and systemic sclerosis (SSc) are rare autoimmune diseases characterized by the presence of CD4+ cytotoxic T cells in the blood as well as inflammation and fibrosis in various organs, but they have no established etiologies. Similar to other autoimmune diseases, the gut microbiome might encode disease-triggering or disease-sustaining factors.

Methods: The gut microbiomes from IgG4-RD and SSc patients as well as healthy individuals with no recent antibiotic treatment were studied by metagenomic sequencing of stool DNA. De novo assembly-based taxonomic and functional characterization, followed by association and accessory gene set enrichment analysis, were applied to describe microbiome changes associated with both diseases.

Results: Microbiomes of IgG4-RD and SSc patients distinctly separated from those of healthy controls: numerous opportunistic pathogenic Clostridium and typically oral Streptococcus species were significantly overabundant, while Alistipes, Bacteroides, and butyrate-producing species were depleted in the two diseases compared to healthy controls. Accessory gene content analysis in these species revealed an enrichment of Th17-activating Eggerthella lenta strains in IgG4-RD and SSc and a preferential colonization of a homocysteine-producing strain of Clostridium bolteae in SSc. Overabundance of the classical mevalonate pathway, hydroxyproline dehydratase, and fibronectin-binding protein in disease microbiomes reflects potential functional differences in host immune recognition and extracellular matrix utilization associated with fibrosis. Strikingly, the majority of species that were differentially abundant in IgG4-RD and SSc compared to controls showed the same directionality in both diseases. Compared with multiple sclerosis and rheumatoid arthritis, the gut microbiomes of IgG4-RD and SSc showed similar signatures; in contrast, the most differentially abundant taxa were not the facultative anaerobes consistently identified in inflammatory bowel diseases, suggesting the microbial signatures of IgG4-RD and SSc do not result from mucosal inflammation and decreased anaerobism.

Conclusions: These results provide an initial characterization of gut microbiome ecology in fibrosis-prone IgG4-RD and SSc and reveal microbial functions that offer insights into the pathophysiology of these rare diseases.
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http://dx.doi.org/10.1186/s13073-021-00853-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919092PMC
February 2021

Mer tyrosine kinase (MerTK) as a possible link between resolution of inflammation and tissue fibrosis in IgG4-related disease.

Rheumatology (Oxford) 2021 Jan 29. Epub 2021 Jan 29.

Università Vita-Salute San Raffaele, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Objectives: IgG4-related disease (IgG4-RD) is a systemic fibro-inflammatory disorder characterized by a dysregulated resolution of inflammation and wound healing response that might develop after an apoptotic insult induced by cytotoxic T lymphocytes (CTLs). Mer receptor tyrosine kinase (MerTK) and its ligand Protein S (ProS1) have a pivotal role in the resolution of inflammation, being implicated in the clearance of apoptotic cells, quenching of the immune response and development of tissue fibrosis. In the present work we aimed to investigate a possible involvement of the MerTK signalling pathway in the pathogenesis of IgG4-RD and development of tissue fibrosis.

Methods: MerTK and ProS1 expression patterns in IgG4-RD lesions were evaluated by immunohistochemistry and immunofluorescence studies. Circulating MerTK+ monocytes, soluble Mer and MerTK ligands were measured in the peripheral blood of IgG4-RD patients and healthy controls by flow cytometry and ELISA, respectively.

Results: MerTK was highly expressed by macrophages infiltrating IgG4-RD lesions. MerTK+ macrophages were more abundant in IgG4-RD than in Sjögren syndrome and interacted with apoptotic cells and ProS1 expressing T and B lymphocytes. Moreover, they expressed the pro-fibrotic cytokine TGF-β and their numbers declined following rituximab induced disease remission. Circulating MerTK+ monocytes, soluble Mer and MerTK ligands were not increased in the peripheral blood of patients with IgG4-RD.

Conclusions: The MerTK-ProS1 axis is activated in IgG4-RD lesions, possibly leading to persistent stimulation of processes involved in the resolution of inflammation and tissue fibrosis.
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http://dx.doi.org/10.1093/rheumatology/keab096DOI Listing
January 2021

Lifetime Allergy Symptoms in IgG4-Related Disease: A Case-Control Study.

Arthritis Care Res (Hoboken) 2020 Dec 20. Epub 2020 Dec 20.

Harvard Medical School, Massachusetts General Hospital in Boston, Boston, MA, USA.

Objective: The etiology of IgG4-related disease (IgG4-RD) is unknown and there has been controversy over the significance of allergic conditions in IgG4-RD. We examined the prevalence of lifetime allergy symptoms in IgG4-RD and the association between these and IgG4-RD.

Methods: We identified IgG4-RD patients and non-IgG4-RD controls without autoimmune conditions seen at a single center. IgG4-RD patients were classified using the ACR/EULAR classification criteria. Allergy symptoms were ascertained by questionnaire. We assessed the association of IgG4-RD features with allergy symptoms. We compared the proportion of cases and controls with allergy symptoms using conditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) after matching cases and controls 1:1 by age and sex.

Results: Lifetime allergy symptoms were reported by 165 (71%) of 231 IgG4-RD cases. Aero-allergen symptoms were most commonly reported (135, 58%) followed by skin allergy symptoms (97, 42%) and food allergy symptoms (47, 20%). IgG4-RD cases with a history of allergy symptoms were more likely to have head and neck involvement (OR 2.0 [95% CI: 1.1-3.6]) and peripheral eosinophilia (OR 3.3 [95% CI: 1.2-9.0]) than those without allergy symptoms. The prevalence of any allergy symptoms was similar between cases and controls (OR 0.7 [95% CI: 0.4-1.1]); this remained consistent after stratifying by head and neck involvement.

Conclusion: Lifetime allergy symptoms are common in IgG4-RD but are not reported more often in IgG4-RD compared to non-IgG4-RD patients without autoimmune conditions. These findings suggest that allergies are not uniquely associated with the pathogenesis or presentation of IgG4-RD.
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http://dx.doi.org/10.1002/acr.24545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8214630PMC
December 2020

CD4CTLs in Fibrosing Mediastinitis Linked to .

J Immunol 2021 02 16;206(3):524-530. Epub 2020 Dec 16.

Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139;

Although fibrotic disorders are frequently assumed to be linked to T cells, quantitative tissue interrogation studies have rarely been performed to establish this link and certainly many fibrotic diseases do not fall within the type 2/allergic disease spectrum. We have previously linked two human autoimmune fibrotic diseases, IgG4-related disease and systemic sclerosis, to the clonal expansion and lesional accumulation of CD4CTLs. In both these diseases T cell accumulation was found to be sparse. Fibrosing mediastinitis linked to infection histologically resembles IgG4-related disease in terms of the inflammatory infiltrate and fibrosis, and it provides an example of a fibrotic disease of infectious origin in which the potentially profibrotic T cells may be induced and reactivated by fungal Ags. We show in this study that, in this human disease, CD4CTLs accumulate in the blood, are clonally expanded, infiltrate into disease lesions, and can be reactivated in vitro by Ags. T cells are relatively sparse at lesional sites. These studies support a general role for CD4CTLs in inflammatory fibrosis and suggest that fibrosing mediastinitis is an Ag-driven disease that may provide important mechanistic insights into the pathogenesis of idiopathic fibrotic diseases.
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http://dx.doi.org/10.4049/jimmunol.2000433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978153PMC
February 2021

Efficacy of Tocilizumab in Patients Hospitalized with Covid-19.

N Engl J Med 2020 12 21;383(24):2333-2344. Epub 2020 Oct 21.

From Massachusetts General Hospital (J.H.S., M.J.F., N.J.S.-B., A.D.F., L.H., A.S.F., N.K.H., B.C.H., C.A.S., M.D., C.M.N., Y.-D.H., T.K.T., Z.D., A.S., R.S.W., A.Y.K., S.S., P.S., T.G.N., C.A.P., S.H.U., D.S.C., M.A.M., J.M.Y., K.A.B., E.M., A.Z., Z.D.D., M.B.B., M.K., K.M.D., J.D., M.M.L., M.K.M.), Brigham and Women's Hospital (A.E.W., S.N., B.N.W.), and Boston Medical Center (N.L., M.S.), Boston, North Shore Medical Center, Salem (R.S., A.M.B., C.C.), Newton-Wellesley Hospital, Newton (H.S., D.S.H.), Beth Israel Lahey Health, Burlington (M.A., M.D.P.), and St. Elizabeth's Medical Center, Brighton (J.F.) - all in Massachusetts.

Background: The efficacy of interleukin-6 receptor blockade in hospitalized patients with coronavirus disease 2019 (Covid-19) who are not receiving mechanical ventilation is unclear.

Methods: We performed a randomized, double-blind, placebo-controlled trial involving patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hyperinflammatory states, and at least two of the following signs: fever (body temperature >38°C), pulmonary infiltrates, or the need for supplemental oxygen in order to maintain an oxygen saturation greater than 92%. Patients were randomly assigned in a 2:1 ratio to receive standard care plus a single dose of either tocilizumab (8 mg per kilogram of body weight) or placebo. The primary outcome was intubation or death, assessed in a time-to-event analysis. The secondary efficacy outcomes were clinical worsening and discontinuation of supplemental oxygen among patients who had been receiving it at baseline, both assessed in time-to-event analyses.

Results: We enrolled 243 patients; 141 (58%) were men, and 102 (42%) were women. The median age was 59.8 years (range, 21.7 to 85.4), and 45% of the patients were Hispanic or Latino. The hazard ratio for intubation or death in the tocilizumab group as compared with the placebo group was 0.83 (95% confidence interval [CI], 0.38 to 1.81; P = 0.64), and the hazard ratio for disease worsening was 1.11 (95% CI, 0.59 to 2.10; P = 0.73). At 14 days, 18.0% of the patients in the tocilizumab group and 14.9% of the patients in the placebo group had had worsening of disease. The median time to discontinuation of supplemental oxygen was 5.0 days (95% CI, 3.8 to 7.6) in the tocilizumab group and 4.9 days (95% CI, 3.8 to 7.8) in the placebo group (P = 0.69). At 14 days, 24.6% of the patients in the tocilizumab group and 21.2% of the patients in the placebo group were still receiving supplemental oxygen. Patients who received tocilizumab had fewer serious infections than patients who received placebo.

Conclusions: Tocilizumab was not effective for preventing intubation or death in moderately ill hospitalized patients with Covid-19. Some benefit or harm cannot be ruled out, however, because the confidence intervals for efficacy comparisons were wide. (Funded by Genentech; ClinicalTrials.gov number, NCT04356937.).
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http://dx.doi.org/10.1056/NEJMoa2028836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646626PMC
December 2020

Prostate and pancreas involvement are linked in IgG4-related disease.

Semin Arthritis Rheum 2020 12 15;50(6):1245-1251. Epub 2020 Sep 15.

Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, MA, United States; Rheumatology Unit, Clinical Epidemiology Unit, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, MA, United States; Harvard Medical School, Boston, MA, United States. Electronic address:

Objective: Prostate involvement by IgG4-related disease (IgG4-RD) is a rarely described organ manifestation and knowledge regarding its frequency and clinical features is limited.

Methods: From a single-center cohort, 168 male patients were examined who satisfied the 2019 ACR/EULAR classification criteria or 2012 consensus histopathologic criteria for IgG4-RD.

Results: Prostate involvement were identified in 25 (15%) of these cases. The majority of patients with IgG4-RD involving the prostate gland (80%) were symptomatic at presentation with incomplete voiding (64%), urinary frequency (52%), and urinary hesitancy (48%) being the most common complaints. The radiologic presentation of prostate disease is most often a focal abnormality suggesting inflammation rather than a mass lesion. While most patients with IgG4-related prostate disease (89%) experienced recurrence after or during glucocorticoid tapering, patients treated with B cell targeted therapy in this series experienced clinical improvement and were tapered off of glucocorticoids. Additionally, patients with IgG4-RD involving the pancreas (p = < 0.001) were more likely to have prostate involvement than were those with other types of organ involvement.

Conclusion: This report provides the first comprehensive clinical description of IgG4-RD involving the prostate gland and links this manifestation with pancreatic involvement.
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http://dx.doi.org/10.1016/j.semarthrit.2020.09.002DOI Listing
December 2020

IgG4-related disease: an update on pathophysiology and implications for clinical care.

Nat Rev Rheumatol 2020 12 16;16(12):702-714. Epub 2020 Sep 16.

Massachusetts General Hospital, Division of Rheumatology, Allergy and Immunology, Boston, MA, USA.

IgG4-related disease (IgG4-RD) has only existed as a unique disease entity since 2003, yet remarkable progress has already been achieved in describing the essential features of the disease. A framework for systematic clinical studies has been created by the development of a quantitative disease activity tool (the IgG4-RD Responder Index) and the validation of classification criteria, both of which were the products of international, multi-centre investigations. In addition, substantial strides have been made in understanding the pathophysiology of IgG4-RD. In particular, the central role of B cells in the disease has been demonstrated by both the robust clinical responsiveness of IgG4-RD to B cell depletion and by the identification of multiple self-antigens that promote B cell expansion. CD4 T cells have also been investigated in detail; CD4 cytotoxic T lymphocytes (suspected of promoting disease) and a specific T follicular helper cell subset that contributes to IgG4 isotype switching have both been defined by multiple groups. The mechanisms by which these immune cells converge on target tissues, interact with fibroblasts and promote tissue remodelling are beginning to be understood and will be an important research focus in the coming years.
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http://dx.doi.org/10.1038/s41584-020-0500-7DOI Listing
December 2020

Reply.

Arthritis Rheumatol 2020 09 20;72(9):1585-1586. Epub 2020 Jul 20.

Ragon Institute of MGH, MIT and Harvard, Cambridge, MA.

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http://dx.doi.org/10.1002/art.41389DOI Listing
September 2020

CD4 and CD8 cytotoxic T lymphocytes may induce mesenchymal cell apoptosis in IgG-related disease.

J Allergy Clin Immunol 2021 01 30;147(1):368-382. Epub 2020 May 30.

Ragon Institute of MGH, MIT, and Harvard, Cambridge, Mass. Electronic address:

Background: IgG-related disease (IgG-RD) is an immune-mediated fibrotic disorder that has been linked to CD4 cytotoxic T lymphocytes (CD4CTLs). The effector phenotype of CD4CTLs and the relevance of both CD8 cytotoxic T lymphocytes (CD8CTLs) and apoptotic cell death remain undefined in IgG-RD.

Objective: We sought to define CD4CTL heterogeneity, characterize the CD8CTL response in the blood and in lesions, and determine whether enhanced apoptosis may contribute to the pathogenesis of IgG-RD.

Methods: Blood analyses were undertaken using flow cytometry, cell sorting, transcriptomic analyses at the population and single-cell levels, and next-generation sequencing for the TCR repertoire. Tissues were interrogated using multicolor immunofluorescence. Results were correlated with clinical data.

Results: We establish that among circulating CD4CTLs in IgG-RD, CD27CD28CD57 cells are the dominant effector subset, exhibit marked clonal expansion, and differentially express genes relevant to cytotoxicity, activation, and enhanced metabolism. We also observed prominent infiltration of granzyme A-expressing CD8CTLs in disease tissues and clonal expansion in the blood of effector/memory CD8 T cells with an activated and cytotoxic phenotype. Tissue studies revealed an abundance of cells undergoing apoptotic cell death disproportionately involving nonimmune, nonendothelial cells of mesenchymal origin. Apoptotic cells showed significant upregulation of HLA-DR.

Conclusions: CD4CTLs and CD8CTLs may induce apoptotic cell death in tissues of patients with IgG-RD with preferential targeting of nonendothelial, nonimmune cells of mesenchymal origin.
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http://dx.doi.org/10.1016/j.jaci.2020.05.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704943PMC
January 2021

Cytotoxic CD4+ T lymphocytes may induce endothelial cell apoptosis in systemic sclerosis.

J Clin Invest 2020 05;130(5):2451-2464

Ragon Institute, Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, USA.

Systemic sclerosis (SSc) is an autoimmune fibrotic disease whose pathogenesis is poorly understood and lacks effective therapies. We undertook quantitative analyses of T cell infiltrates in the skin of 35 untreated patients with early diffuse SSc and here show that CD4+ cytotoxic T cells and CD8+ T cells contribute prominently to these infiltrates. We also observed an accumulation of apoptotic cells in SSc tissues, suggesting that recurring cell death may contribute to tissue damage and remodeling in this fibrotic disease. HLA-DR-expressing endothelial cells were frequent targets of apoptosis in SSc, consistent with the prominent vasculopathy seen in patients with this disease. A circulating effector population of cytotoxic CD4+ T cells, which exhibited signatures of enhanced metabolic activity, was clonally expanded in patients with systemic sclerosis. These data suggest that cytotoxic T cells may induce the apoptotic death of endothelial and other cells in systemic sclerosis. Cell loss driven by immune cells may be followed by overly exuberant tissue repair processes that lead to fibrosis and tissue dysfunction.
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http://dx.doi.org/10.1172/JCI131700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190971PMC
May 2020

Immune mechanisms of fibrosis and inflammation in IgG4-related disease.

Curr Opin Rheumatol 2020 03;32(2):146-151

Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Cambridge.

Purpose Of Review: To summarize recent advances in the understanding of the pathogenesis of IgG4-related disease.

Recent Findings: Limited data exist to explain genetic susceptibility to IgG4-related disease and the underlying triggers for this disease have not yet been identified. Cytotoxic CD4 T cells and activated B cells infiltrate affected organs and express proinflammatory and profibrotic molecules. Antigen presented by activated B cells likely reactivates cytotoxic CD4 T cells in disease tissues and these T cells in turn induce the targeted apoptotic death of host cells in certain organs - which presumably present the same antigenic peptide on human leukocyte antigen class II molecules of relevance that was also presented on B cells during reactivation. A subsequent exaggerated tissue remodeling process is orchestrated by cytokines, chemokines, and enzymes secreted by both activated B cells and CD4CTLs. These molecules induce an overexuberant repair process resulting in fibrosis and loss of target organ function.

Summary: In IgG4-related disease, presumably self-reactive cytotoxic CD4 T cells infiltrate tissues, are reactivated by T cells and induce apoptotic death. Molecules secreted by activated B cells and by CD4CTLs drive an exaggerated wound healing response resulting in fibrosis and compromised tissue function.
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http://dx.doi.org/10.1097/BOR.0000000000000686DOI Listing
March 2020

The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease.

Ann Rheum Dis 2020 01 3;79(1):77-87. Epub 2019 Dec 3.

Massachusetts General Hospital Rheumatology Unit, Harvard Medical School, Boston, Massachusetts, USA

IgG4-related disease (IgG4-RD) can cause fibroinflammatory lesions in nearly any organ. Correlation among clinical, serological, radiological and pathological data is required for diagnosis. This work was undertaken to develop and validate an international set of classification criteria for IgG4-RD. An international multispecialty group of 86 physicians was assembled by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). Investigators used consensus exercises; existing literature; derivation and validation cohorts of 1879 subjects (1086 cases, 793 mimickers); and multicriterion decision analysis to identify, weight and test potential classification criteria. Two independent validation cohorts were included. A three-step classification process was developed. First, it must be demonstrated that a potential IgG4-RD case has involvement of at least one of 11 possible organs in a manner consistent with IgG4-RD. Second, exclusion criteria consisting of a total of 32 clinical, serological, radiological and pathological items must be applied; the presence of any of these criteria eliminates the patient from IgG4-RD classification. Third, eight weighted inclusion criteria domains, addressing clinical findings, serological results, radiological assessments and pathological interpretations, are applied. In the first validation cohort, a threshold of 20 points had a specificity of 99.2% (95% CI 97.2% to 99.8%) and a sensitivity of 85.5% (95% CI 81.9% to 88.5%). In the second, the specificity was 97.8% (95% CI 93.7% to 99.2%) and the sensitivity was 82.0% (95% CI 77.0% to 86.1%). The criteria were shown to have robust test characteristics over a wide range of thresholds. ACR/EULAR classification criteria for IgG4-RD have been developed and validated in a large cohort of patients. These criteria demonstrate excellent test performance and should contribute substantially to future clinical, epidemiological and basic science investigations.
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http://dx.doi.org/10.1136/annrheumdis-2019-216561DOI Listing
January 2020

The 2019 American College of Rheumatology/European League Against Rheumatism Classification Criteria for IgG4-Related Disease.

Arthritis Rheumatol 2020 01 2;72(1):7-19. Epub 2019 Dec 2.

Massachusetts General Hospital, Boston.

Objective: IgG4-related disease (IgG4-RD) can cause fibroinflammatory lesions in nearly any organ. Correlation among clinical, serologic, radiologic, and pathologic data is required for diagnosis. This work was undertaken to develop and validate an international set of classification criteria for IgG4-RD.

Methods: An international multispecialty group of 86 physicians was assembled by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). Investigators used consensus exercises, existing literature, derivation and validation cohorts of 1,879 subjects (1,086 cases, 793 mimickers), and multicriterion decision analysis to identify, weight, and test potential classification criteria. Two independent validation cohorts were included.

Results: A 3-step classification process was developed. First, it must be demonstrated that a potential IgG4-RD case has involvement of at least 1 of 11 possible organs in a manner consistent with IgG4-RD. Second, exclusion criteria consisting of a total of 32 clinical, serologic, radiologic, and pathologic items must be applied; the presence of any of these criteria eliminates the patient from IgG4-RD classification. Third, 8 weighted inclusion criteria domains, addressing clinical findings, serologic results, radiology assessments, and pathology interpretations, are applied. In the first validation cohort, a threshold of 20 points had a specificity of 99.2% (95% confidence interval [95% CI] 97.2-99.8%) and a sensitivity of 85.5% (95% CI 81.9-88.5%). In the second, the specificity was 97.8% (95% CI 93.7-99.2%) and the sensitivity was 82.0% (95% CI 77.0-86.1%). The criteria were shown to have robust test characteristics over a wide range of thresholds.

Conclusion: ACR/EULAR classification criteria for IgG4-RD have been developed and validated in a large cohort of patients. These criteria demonstrate excellent test performance and should contribute substantially to future clinical, epidemiologic, and basic science investigations.
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http://dx.doi.org/10.1002/art.41120DOI Listing
January 2020

Diagnostic Pitfalls in Immunology Testing.

Clin Lab Med 2019 12 10;39(4):567-578. Epub 2019 Sep 10.

Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, MA, USA; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA. Electronic address:

Immunology testing is relevant for the diagnosis of many autoimmune conditions. However, diagnostic pitfalls arise owing to incorrect interpretation of results and incomplete understanding of the underlying technique or immune-mediated condition. Here, we review the diagnostic considerations related to commonly used immunology tests. Specifically, we summarize the caveats pertinent to the interpretation of rheumatoid factor, antinuclear antibodies, antiphospholipid antibodies, antineutrophil cytoplasmic antibodies, and serum IgG4 testing.
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http://dx.doi.org/10.1016/j.cll.2019.07.005DOI Listing
December 2019

Disease Severity Linked to Increase in Autoantibody Diversity in IgG4-Related Disease.

Arthritis Rheumatol 2020 04 10;72(4):687-693. Epub 2020 Feb 10.

Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts.

Objective: Four autoantigens have been described recently in IgG4-related disease (IgG4-RD): prohibitin, annexin A11, laminin 511-E8, and galectin-3. However, no external validation has been performed, and the possibility that some individuals break tolerance to more than 1 autoantigen has not been explored. We undertook this study to evaluate the relative frequencies of antibody responses against these autoantigens in order to explore the role of adaptive immune response in IgG4-RD.

Methods: Autoantibody responses against prohibitin, annexin A11, and laminin 511-E8 were measured among a clinically diverse cohort of IgG4-RD patients (n = 100) using enzyme-linked immunosorbent assays. Autoantibody responses were correlated with disease severity and organ distribution.

Results: The frequencies of IgG4 autoantibody responses against prohibitin (10%), annexin A11 (12%), and laminin 511-E8 (7%) were not significantly different from those of controls. A portion of the cohort (n = 86) had been analyzed previously at our center for anti-galectin-3 antibody responses, with 25 patients (29%) having IgG4 anti-galectin-3 antibodies. Of these 86 patients, 32 (37%) had IgG4 antibodies to ≥1 of the 4 autoantigens and 12 (14%) showed reactivity with ≥2 of the tested antigens. The subset of patients with ≥2 autoantibodies had higher total levels of IgG1, IgG2, IgG4, and C-reactive protein, were more commonly hypocomplementemic, and were more likely to have visceral organ involvement.

Conclusion: Antibodies against prohibitin, annexin A11, and laminin 511-E8 were found in only a small portion of patients with IgG4-RD. A subset of IgG4-RD patients, however, had IgG4 antibodies against ≥2 autoantigens. These patients presented with robust IgG subclass elevations, complement consumption, and visceral organ involvement. This broader break in immunologic tolerance in IgG4-RD was associated with more severe disease.
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http://dx.doi.org/10.1002/art.41140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113109PMC
April 2020

Immunoglobulin G4-related Disease.

Clin Chest Med 2019 09;40(3):583-597

Rheumatology Unit, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.

Immunoglobulin G4 (IgG4)-Related Disease (IgG4-RD) can cause fibroinflammatory lesions in nearly any organ and lead to organ dysfunction and irreversible damage. In addition to frequent involvement of the salivary glands, lacrimal glands, and/or pancreas, IgG4-RD often affects the chest. Thoracic manifestations include lung nodules and consolidations, pleural thickening, aortitis, and lymphadenopathy. The diagnosis is made after careful clinicopathologic correlation because there is no single diagnostic test with excellent sensitivity or specificity. Biopsy of pulmonary lesions can be useful for distinguishing IgG4-RD from common mimickers. Immunosuppressive regimens, such as glucocorticoids and/or glucocorticoid-sparing agents, form the cornerstone of treatment.
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http://dx.doi.org/10.1016/j.ccm.2019.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7133392PMC
September 2019

B lymphocytes directly contribute to tissue fibrosis in patients with IgG-related disease.

J Allergy Clin Immunol 2020 03 15;145(3):968-981.e14. Epub 2019 Jul 15.

Ragon Institute of MGH, MIT, and Harvard, Massachusetts General Hospital, Harvard Medical School, Boston, Mass.

Background: IgG-related disease (IgG-RD) is a fibroinflammatory condition marked by rapid clinical improvement after selective depletion of B lymphocytes with rituximab. This feature suggests that B cells might participate in fibrogenesis and wound healing.

Objective: In the present work we aimed to demonstrate that B lymphocytes contribute directly to tissue fibrosis in patients with IgG-RD.

Methods: Total circulating CD19 B lymphocytes, naive B cells, memory B cells, or plasmablasts from patients with IgG-RD were cultivated with human fibroblasts. Profibrotic soluble factors and collagen production in cocultures were assessed by using ELISAs and Luminex assays. RNA sequencing and quantitative RT-PCR were used to assess fibroblast activation in the presence of B cells, as well as induction of profibrotic pathways in B-cell subsets. Relevant profibrotic and inflammatory molecules were confirmed in vitro by using functional experiments and on IgG-RD tissue sections by using multicolor immunofluorescence studies.

Results: B cells from patients with IgG-RD (1) produced the profibrotic molecule platelet-derived growth factor B and stimulated collagen production by fibroblasts; (2) expressed enzymes implicated in extracellular matrix remodeling, such as lysyl oxidase homolog 2; (3) produced the chemotactic factors CCL4, CCL5, and CCL11; and (4) induced production of these same chemokines by activated fibroblasts. Plasmablasts expressed sets of genes implicated in fibroblast activation and proliferation and therefore represent cells with intrinsic profibrotic properties.

Conclusion: We have demonstrated that B cells contribute directly to tissue fibrosis in patients with IgG-RD. These unanticipated profibrotic properties of B lymphocytes, particularly plasmablasts, might be relevant for fibrogenesis in patients with other fibroinflammatory disorders and for wound-healing processes in physiologic conditions.
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http://dx.doi.org/10.1016/j.jaci.2019.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960365PMC
March 2020

Phospholipase A2 receptor-associated membranous nephropathy in a patient with IgG4-related disease: A case report.

Medicine (Baltimore) 2019 May;98(20):e15616

Division of Nephrology.

Rationale: IgG4-related disease (IgG4-RD) is a multiorgan disease of unestablished prevalence that is characterized histopathologically by a dense lymphoplasmacytic infiltrate enriched with IgG4-expressing plasma cells and associated with storiform fibrosis. Tubulointerstitial nephritis (TIN) is the most common renal manifestation of IgG4-RD, but membranous nephropathy (MN) has also been described and often occurs in the context of concurrent TIN. Patients with IgG4-related MN have been characteristically negative for autoantibodies to the phospholipase A2 receptor (PLA2R).

Patient Concerns: A 45-year-old man presented with abdominal pain and lower extremity edema.

Diagnosis: Histopathological evaluation of pancreas and liver biopsies established a diagnosis of IgG4-RD. Renal biopsy confirmed a diagnosis of PLA2R-associated MN without evidence of concurrent TIN.

Interventions: The patient was treated with rituximab, a short course of low-dose, oral cyclophosphamide, and a rapid glucocorticoid taper.

Outcomes: The patient achieved remission of MN after 8 months of therapy and maintained remission of IgG4-RD.

Lessons: PLA2R-associated MN may be a rare manifestation of IgG4-RD. Systematic evaluation of larger cohorts of IgG4-RD patients for the presence of PLA2R autoantibodies and the investigation of PLA2R-associated MN cohorts for evidence of IgG4-RD would facilitate the understanding of the nature of the relationship between these observations.
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http://dx.doi.org/10.1097/MD.0000000000015616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531114PMC
May 2019

IgG4-related disease: Association with a rare gene variant expressed in cytotoxic T cells.

Mol Genet Genomic Med 2019 06 16;7(6):e686. Epub 2019 Apr 16.

Vanderbilt Center for Undiagnosed Disease, Vanderbilt University, Nashville, Tennessee.

Background: Family screening of a 48-year-old male with recently diagnosed IgG4-related disease (IgG4-RD) revealed unanticipated elevations in plasma IgG4 in his two healthy teenaged sons.

Methods: We performed gene sequencing, immune cell studies, HLA typing, and analyses of circulating cytotoxic CD4+ T lymphocytes and plasmablasts to seek clues to pathogenesis. DNA from a separate cohort of 99 patients with known IgG4-RD was also sequenced for the presence of genetic variants in a specific gene, FGFBP2.

Results: The three share a previously unreported heterozygous single base deletion in fibroblast growth factor binding protein type 2 (FGFBP2), which causes a frameshift in the coding sequence. The FGFBP2 protein is secreted by cytotoxic T-lymphocytes and binds fibroblast growth factor. The variant sequence in the FGFBP2 protein is predicted to form a disordered random coil rather than a helical-turn-helix structure, unable to adopt a stable conformation. The proband and the two sons had 5-10-fold higher numbers of circulating cytotoxic CD4 + T cells and plasmablasts compared to matched controls. The three members also share a homozygous missense common variant in FGFBP2 found in heterozygous form in ~40% of the population. This common variant was found in 73% of an independent, well characterized IgG4-RD cohort, showing enrichment in idiopathic IgG4-RD.

Conclusions: The presence of a shared deleterious variant and homozygous common variant in FGFBP2 in the proband and sons strongly implicates this cytotoxic T cell product in the pathophysiology of IgG4-RD. The high prevalence of a common FGFBP2 variant in sporadic IgG4-RD supports the likelihood of participation in disease.
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http://dx.doi.org/10.1002/mgg3.686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565556PMC
June 2019

Clinical phenotypes of IgG4-related disease: an analysis of two international cross-sectional cohorts.

Ann Rheum Dis 2019 03 5;78(3):406-412. Epub 2019 Jan 5.

Rheumatology Unit, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, Massachusetts, USA.

Objective: IgG4-related disease (IgG4-RD) is a heterogeneous, multiorgan condition of unclear aetiology that can cause organ failure. Difficulty recognising IgG4-RD contributes to diagnostic delays. We sought to identify key IgG4-RD phenotypes.

Methods: We used two cross-sectional studies assembled by an international, multispecialty network of IgG4-RD specialists who submitted 765 cases to derive and replicate phenotypic groups. Phenotype groups of disease manifestations and key covariate distributions across the identified groups were measured using latent class analysis.

Results: In the derivation cohort (n=493), we identified four groups with distinct manifestations: Group 1 (31%), Pancreato-Hepato-Biliary disease; Group 2 (24%), Retroperitoneal Fibrosis and/or Aortitis; Group 3 (24%), Head and Neck-Limited disease and Group 4 (22%), classic Mikulicz syndrome with systemic involvement. We replicated the identification of four phenotype groups in the replication cohort. Compared with cases in Groups 1, 2 and 4, respectively, cases in Group 3 were more likely to be female (OR 11.60 (95% CI 5.39 to 24.98), 10.35 (95% CI 4.63 to 23.15) and 9.24 (95% CI 3.53 to 24.20)) and Asian (OR 6.68 (95% CI 2.82 to 15.79), 7.43 (95% CI 2.97 to 18.56) and 6.27 (95% CI 2.27 to 17.29)). Cases in Group 4 had a higher median serum IgG4 concentration (1170 mg/dL) compared with groups 1-3 (316, 178 and 445 mg/dL, respectively, p<0.001).

Conclusion: We identified four distinctive IgG4-RD phenotypes according to organ involvement. Being Asian or female may predispose individuals to head and neck-limited disease. These phenotypes serve as a framework for identifying IgG4-RD and studying its aetiology and optimal treatment.
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http://dx.doi.org/10.1136/annrheumdis-2018-214603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996288PMC
March 2019

Rituximab for idiopathic and IgG4-related retroperitoneal fibrosis.

Medicine (Baltimore) 2018 Oct;97(42):e12631

Department of Medicine.

Retroperitoneal fibrosis (RPF) refers to a fibro-inflammatory lesion in the retroperitoneum, often anterolateral to the aorta. Most cases are due to IgG4-related disease (IgG4-RD) or are idiopathic. RPF can lead to severe morbidity. Treatment strategies remain poorly-defined. We evaluated the efficacy and safety of rituximab (RTX) for idiopathic or IgG4-related RPF.We retrospectively reviewed the records of patients who had RPF treated with RTX. Treatment response was determined by assessing changes in both clinical features, including symptoms and laboratory measurements, as well as in the radiographic dimensions of the lesion.Twenty-six patients with IgG4-related (n = 19) or idiopathic RPF (n = 7) were identified. Patients without histopathological evidence of IgG4-RD on either retroperitoneal biopsies or sampling of extra-retroperitoneal organs were considered to have idiopathic RPF. Of the 26 patients, 19 (73%) received RTX without additional glucocorticoids. All 19 patients who presented with pain reported symptomatic improvement following RTX. Among 25 patients with follow-up imaging, 22 (88%) had radiologic improvement. Among 10 patients with ureteral stents and/or percutaneous nephrostomy tubes, 4 (40%) underwent successful stent or tube removal. Responses to treatment were similar among those treated with RTX monotherapy and those treated with RTX and glucocorticoids. RTX was generally well tolerated, but 3 (12%) patients experienced severe infections.In this study, RTX for RPF led to resolution of symptoms in all patients and radiographic improvement in the majority. Prospective studies of RTX for RPF are indicated.
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http://dx.doi.org/10.1097/MD.0000000000012631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211888PMC
October 2018

Identification of galectin-3 as an autoantigen in patients with IgG-related disease.

J Allergy Clin Immunol 2019 02 29;143(2):736-745.e6. Epub 2018 May 29.

Division of Rheumatology, Allergy, & Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Mass; Ragon Institute of MGH, MIT and Harvard, Cambridge, Mass. Electronic address:

Background: The antigenic trigger that drives expansion of circulating plasmablasts and CD4 cytotoxic T cells in patients with IgG-related disease (IgG-RD) is presently unknown.

Objective: We sought to sequence immunoglobulin genes from single-cell clones of dominantly expanded plasmablasts and generate recombinant human mAbs to identify relevant antigens in patients with IgG-RD by using mass spectrometry.

Methods: Paired heavy and light chain cDNAs from dominant plasmablast clones were expressed as mAbs and used to purify antigens by using immunoaffinity chromatography. Affinity-purified antigens were identified by using mass spectrometry and validated by means of ELISA. Plasma levels of the antigen of interest were also determined by using ELISA.

Results: mAbs expressed from the 2 dominant plasmablast clones of a patient with multiorgan IgG-RD stained human pancreatic tissue sections. Galectin-3 was identified as the antigen specifically recognized by both mAbs. Anti-galectin-3 autoantibody responses were predominantly of the IgG isotype (28% of the IgG-RD cohort, P = .0001) and IgE isotype (11% of the IgG-RD cohort, P = .009). No significant responses were seen from the IgG, IgG, or IgG isotypes. IgG anti-galectin-3 autoantibodies correlated with increased plasma galectin-3 levels (P = .001), lymphadenopathy (P = .04), total IgG level increase (P = .05), and IgG level increase (P = .03).

Conclusion: Affinity chromatography using patient-derived mAbs identifies relevant autoantigens in patients with IgG-RD. IgG galectin-3 autoantibodies are present in a subset of patients with IgG-RD and correlate with galectin-3 plasma levels. The marked increases in levels of circulating IgG and IgE observed clinically are, at least in part, caused by the development of IgG- and IgE-specific autoantibody responses.
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http://dx.doi.org/10.1016/j.jaci.2018.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265117PMC
February 2019

A CD8α- Subset of CD4+SLAMF7+ Cytotoxic T Cells Is Expanded in Patients With IgG4-Related Disease and Decreases Following Glucocorticoid Treatment.

Arthritis Rheumatol 2018 07 20;70(7):1133-1143. Epub 2018 May 20.

Università Vita-Salute San Raffaele and IRCCS San Raffaele Scientific Institute, Milan, Italy.

Objective: An unconventional population of CD4+ signaling lymphocytic activation molecule family member 7-positive (SLAMF7+) cytotoxic effector memory T (T ) cells (CD4+ cytotoxic T lymphocytes [CTLs]) has been linked causally to IgG4-related disease (IgG4-RD). Glucocorticoids represent the first-line therapeutic approach in patients with IgG4-RD, but their mechanism of action in this specific condition remains unknown. We undertook this study to determine the impact of glucocorticoids on CD4+ CTLs in IgG4-RD.

Methods: Expression of CD8α, granzyme A, perforin, and SLAMF7 within the effector memory compartment of CD45RO+ (T ) and CD45RA+ effector memory T (T ) CD4+ cells was quantified by flow cytometry in 18 patients with active IgG4-RD, both at baseline and after 6 months of glucocorticoid treatment. Eighteen healthy subjects were studied as controls. Next-generation sequencing of the T cell receptor α- and β-chain gene was performed on circulating CD4+ CTLs from patients with IgG4-RD before and after treatment and in affected tissues.

Results: Circulating CD4+ T and T cells were not expanded in IgG4-RD patients compared to healthy controls. CD4+SLAMF7+ T cells (but not T cells) were significantly increased among IgG4-RD patients. Within CD4+SLAMF7+ T cells, CD8α- cells but not CD8α cells were elevated in IgG4-RD patients. The same dominant clones of CD8α-CD4+SLAMF7+ T cells found in peripheral blood were also identified in affected tissue. CD8α- and CD8α CD4+SLAMF7+ T cells both expressed cytolytic molecules. Clonally expanded CD8α- but not CD8α CD4+SLAMF7+ T cells decreased following glucocorticoid-induced disease remission.

Conclusion: A subset of CD8α-CD4+SLAMF7+ cytotoxic T cells is oligoclonally expanded in patients with active IgG4-RD. This T cell population contracts following glucocorticoid-induced remission. Further characterization of this cell population may provide prognostic information and targets for therapeutic intervention.
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http://dx.doi.org/10.1002/art.40469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019645PMC
July 2018

An International Multispecialty Validation Study of the IgG4-Related Disease Responder Index.

Arthritis Care Res (Hoboken) 2018 11;70(11):1671-1678

Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

Objective: IgG4-related disease (IgG4-RD) can cause fibroinflammatory lesions in nearly any organ, leading to organ dysfunction and failure. The IgG4-RD Responder Index (RI) was developed to help investigators assess the efficacy of treatment in a structured manner. The aim of this study was to validate the RI in a multinational investigation.

Methods: The RI guides investigators through assessments of disease activity and damage in 25 domains, incorporating higher weights for disease manifestations that require urgent treatment or that worsen despite treatment. After a training exercise, investigators reviewed 12 written IgG4-RD vignettes based on real patients. Investigators calculated both an RI score as well as a physician's global assessment (PhGA) score for each vignette. In a longitudinal assessment, 3 investigators used the RI in 15 patients with newly active disease who were followed up over serial visits after treatment. We assessed interrater and intrarater reliability, precision, validity, and responsiveness.

Results: The 26 physician investigators included representatives from 6 specialties and 9 countries. The interrater and intrarater reliability of the RI was strong (0.89 and 0.69, respectively). Correlations (construct validity) between the RI and PhGA were high (Spearman's r = 0.9, P < 0.0001). The RI was sensitive to change (discriminant validity). Following treatment, there was significant improvement in the RI score (mean change 10.5 [95% confidence interval (95% CI) 5.4-12], P < 0.001), which correlated with the change in the PhGA. Urgent disease and damage were captured effectively.

Discussion: In this international, multispecialty study, we observed that the RI is a valid and reliable disease activity assessment tool that can be used to measure response to therapy.
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http://dx.doi.org/10.1002/acr.23543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6098740PMC
November 2018

Getting with the program in type 1 diabetes mellitus.

Sci Immunol 2018 01;3(19)

Department of Medicine, Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, MA 02139, USA. Email:

Transcriptomic studies reveal defective costimulation via PD-L1 to explain the autoreactive phenotype seen in type 1 diabetes mellitus.
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http://dx.doi.org/10.1126/sciimmunol.aar8621DOI Listing
January 2018

Reply.

Arthritis Rheumatol 2018 02 3;70(2):318. Epub 2018 Jan 3.

Massachusetts General Hospital, Boston, MA.

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http://dx.doi.org/10.1002/art.40362DOI Listing
February 2018
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