Systemic lupus erythematosus sera inhibit antigen presentation by macrophages to T cells

Brożek, Celestyn M.; Hoffman, Charles L.; Savage, Susan; Searles, Robert P.

doi:10.1016/0090-1229(88)90192-4

Cited by 12 publications

(4 citation statements)

References 37 publications

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“…This is consistent with our observation of reduced Ag-specific CD4 activation by SLE.yaa splenocytes, which supports previous reports of myeloid dysfunction in SLE patients (116120). Although prior studies attribute this to serologic factors present in SLE (117,121,122), our coculture experiments are consistent with myeloid cellintrinsic dysfunction, although they are limited by use of a heterogenous APC population. Alternatively, reduced Ag-specific CD4 activation in our coculture assay might be due to differences in APC coinhibitory receptor expression or frequency in SLE.yaa mice.…”

Section: Discussionsupporting

confidence: 84%

Lupus Susceptibility Loci Predispose Mice to Clonal Lymphocytic Responses and Myeloid Expansion

Akama-Garren

Carroll

2022

The Journal of Immunology

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to generate a single-cell dataset of a spontaneous mouse model of lupus. Singlecell sequencing captured vast changes in immune cell heterogeneity and phenotype, including identification of novel myeloid subpopulations associated with lupus. Metabolic modeling revealed opposing changes in metabolic activity between B cells and myeloid cells in lupus-prone mice. BCR tracing identified clonal expansion toward the plasma cell (PC) compartment, and algorithmic analyses of the TCR repertoire were capable of separating CD4 clonotypes based on genotype. Ligandreceptor interaction analysis highlighted signaling relationships between innate and adaptive immune cell types that may contribute to loss of tolerance.Functional validation using coculture experiments demonstrated decreased ability of autoimmune splenocytes to stimulate Ag-specific CD4 responses. As the first single-cell atlas of lupus-prone mice to our knowledge, our dataset serves as a resource for therapeutic target discovery and biological characterization of autoantibody-mediated disease. Materials and Methods MiceC57BL/6J (B6, JAX no. 000664), B6.SJL (CD45.1, JAX no. 002014), and SLE.yaa mice (JAX no. 021569) were obtained from The Jackson Laboratory. OT-II mice were a gift from Gabriel Victora (Rockefeller University) and crossed onto a CD45.1 background. Mice were maintained at Harvard Medical School in an American Association for the Accreditation of Laboratory Animal Careaccredited facility. Fifteen-week-old male mice were used for all experiments unless noted otherwise. All animal experiments were approved by the Institutional Animal Care and Use Committee of Harvard Medical School (IS111). ImmunizationImmunization was performed by i.p. injection of 100 mg of 4-hydroxy-3nitrophenyl acetyl hapten conjugated to OVA (NP-OVA, Biosearch Technologies) in 50 ml of HBSS emulsified with 50 ml of Imject alum adjuvant (Thermo Scientific). Three weeks after immunization, mice were boosted with i.p. 100 mg NP-OVA in 100 ml of HBSS (Corning Life Sciences). Mice were sacrificed 10 d after booster immunization.

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Section: Discussionsupporting

confidence: 84%

Lupus Susceptibility Loci Predispose Mice to Clonal Lymphocytic Responses and Myeloid Expansion

Akama-Garren

Carroll

2022

The Journal of Immunology

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“…Another indirect effect, possibly leading to decreased T-cell activation is poor antigen presentation, which is of special importance in current experimental setup using whole blood samples and stimulation with exogenous antigens. Previous studies have pointed to defects in antigen presentation in SLE patients [ 44 , 45 ], which would influence the T-cell activation. Since Larsen et al found normal levels of CMV-specific T-cells in SLE patients with normal effector responses using CMV-MHCI tetramers [ 26 ], our results on decreased T-cell activation upon CMVpp52 stimulation possibly reflect poor antigen presentation in the SLE patients.…”

Section: Discussionmentioning

confidence: 99%

Immune responses to an early lytic cytomegalovirus antigen in systemic lupus erythematosus patients: T-cell responses, cytokine secretions and antibody status

et al. 2018

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We investigated immune responses to a lytic cytomegalovirus antigen (CMVpp52), and to a lytic human herpes virus (HHV) 6 antigen (HHV6p41), in systemic lupus erythematosus (SLE) patients and healthy controls (HCs), in order to clarify if the previously established impaired responses to Epstein-Barr virus (EBV) in SLE patients is a general defect in their responses against (all) HHVs. Multiplex Luminex technology results showed a normal induction of five quantified cytokines (interferon γ, interleukin(IL)12, IL17, IL10, and tumor necrosis factor α) in SLE patients compared to HCs upon stimulation with CMVpp52 and HHV6p41. However, flow cytometric results showed a reduced upregulation of the activation marker CD69 on T-cells from SLE patients (n = 17) compared to HCs (n = 17) upon stimulation with CMVpp52, indicating limited or defective CMVpp52-specific T-cells and/or poor antigen-presentation in SLE patients, and thereby possibly decreased control of the CMV infection. In conclusion, the dysfunctional immune response against EBV previously established in SLE patients does not seem to apply to the same degree regarding the immune responses against CMV or HHV6. Results designate that the main contributing HHV agent in development or exacerbation of SLE (in genetically predisposed individuals) is the previously determined uncontrolled EBV infection, and to a lesser extent CMV infection, and probably with no involvement of HHV6 infection.

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“…137 Furthermore, previous research has shown that serum from patients with SLE has IgG and IgM that alter the antigen-presenting function of MCs that contribute to a lower antigenic response in these patients. 138 Recently, through the examination of splenic tissue from patients with SLE, a reduction in the expression and phagocytic function of the marginal zone MCs was observed, which are implicated in the clearance of apoptotic cells and induction of tolerance through the production of TGF-B and IL-10. Also, a recently discovered mechanism of autophagy was identified, and it is known as microtubule-associated protein 1A/1B-light chain 3-associated phagocytosis (LAP).…”

Section: Macrophagesmentioning

confidence: 99%

Section: Systemic Lupus Erythematosusmentioning

confidence: 99%

Rheumatoid arthritis and systemic lupus erythematosus: Pathophysiological mechanisms related to innate immune system

et al. 2019

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Rheumatoid arthritis and systemic lupus erythematosus are two highly prevalent autoimmune diseases that generate disability and low quality of life. The innate immune system, a long-forgotten issue in autoimmune diseases, is becoming increasingly important and represents a new focus for the treatment of these entities. This review highlights the role that innate immune system plays in the pathophysiology of rheumatoid arthritis and systemic lupus erythematosus. The role of the innate immune system in rheumatoid arthritis and systemic lupus erythematosus pathophysiology is not only important in early stages but is essential to maintain the immune response and to allow disease progression. In rheumatoid arthritis, genetic and environmental factors are involved in the initial stimulation of the innate immune response in which macrophages are the main participants, as well as fibroblast-like synoviocytes. In systemic lupus erythematosus, all the cells contribute to the inflammatory response, but the complement system is the major effector of the inflammatory process. Detecting alterations in the normal function of these cells, besides its contribution to the understanding of the pathophysiology of autoimmune diseases, could help to establish new treatment strategies for these diseases.

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Systemic lupus erythematosus sera inhibit antigen presentation by macrophages to T cells

Cited by 12 publications

References 37 publications

Lupus Susceptibility Loci Predispose Mice to Clonal Lymphocytic Responses and Myeloid Expansion

Lupus Susceptibility Loci Predispose Mice to Clonal Lymphocytic Responses and Myeloid Expansion

Immune responses to an early lytic cytomegalovirus antigen in systemic lupus erythematosus patients: T-cell responses, cytokine secretions and antibody status

Rheumatoid arthritis and systemic lupus erythematosus: Pathophysiological mechanisms related to innate immune system

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