B Cell Metabolism and Autophagy in Autoimmunity

Raza, Iwan G. A.; Clarke, Adam J.

doi:10.3389/fimmu.2021.681105

Cited by 51 publications

(43 citation statements)

References 145 publications

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“…The latter, which represent the terminally differentiated cells of the humoral immune response, are the main effector B cells that expand in acute SLE ( 49 ). Of note, autophagy has been seen to play a general role in the late stages of B cell activation and subsequent PC differentiation ( 50 – 52 ). In the experimental in vitro setting we applied, naïve B cells were not able to efficiently class-switch and therefore the fine specificity of secreted Ig could not be identified.…”

Section: Resultsmentioning

confidence: 99%

P140 Peptide Leads to Clearance of Autoreactive Lymphocytes and Normalizes Immune Response in Lupus-Prone Mice

et al. 2022

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In systemic lupus erythematosus, T cells display multiple abnormalities. They are abnormally activated, secrete pro-inflammatory cytokines, help B cells to generate pathogenic autoantibodies, and provoke the accumulation of autoreactive memory T cells. P140, a synthetic peptide evaluated in phase-III clinical trials for lupus, binds HSPA8/HSC70 chaperone protein. In vitro and in vivo, it interferes with hyperactivated chaperone-mediated autophagy, modifying overexpression of major histocompatibility complex class II molecules and antigen presentation to autoreactive T cells. Here, we show that in P140-treated lupus mice, abnormalities affecting T and B cells are no longer detectable in secondary lymphoid tissue and peripheral blood. Data indicate that P140 acts by depleting hyper-activated autoreactive T and B cells and restores normal immune homeostasis. Our findings suggest that P140 belongs to a new family of non-immunosuppressive immunoregulators that do not correct T and B cell abnormalities but rather contribute to the clearance of deleterious T and B cells.

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Section: Resultsmentioning

confidence: 99%

P140 Peptide Leads to Clearance of Autoreactive Lymphocytes and Normalizes Immune Response in Lupus-Prone Mice

et al. 2022

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“…However, there is another side to mTOR, autophagy, B cells, and autoimmunity. As B cells can present antigen and autophagy, linked to antigen presentation [ 102 ], autophagy inducers could also promote autoimmunity, as in the case of citrullinated peptides, which are relevant in rheumatoid arthritis [ 103 ]. Further, autophagy of B cells is found to increase in murine models of lupus even prior to disease onset [ 104 ], and this increase is greater in immature B cells; autophagy of B cells is also increased in patients with systemic lupus erythematosus.…”

Section: Specific Role Of Mtor On the Biological Process Of Autophagy...mentioning

confidence: 99%

The mTOR Signaling Pathway in Multiple Sclerosis; from Animal Models to Human Data

Vakrakou

Alexaki

Brinia

et al. 2022

IJMS

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This article recapitulates the evidence on the role of mammalian targets of rapamycin (mTOR) complex pathways in multiple sclerosis (MS). Key biological processes that intersect with mTOR signaling cascades include autophagy, inflammasome activation, innate (e.g., microglial) and adaptive (B and T cell) immune responses, and axonal and neuronal toxicity/degeneration. There is robust evidence that mTOR inhibitors, such as rapamycin, ameliorate the clinical course of the animal model of MS, experimental autoimmune encephalomyelitis (EAE). New, evolving data unravel mechanisms underlying the therapeutic effect on EAE, which include balance among T-effector and T-regulatory cells, and mTOR effects on myeloid cell function, polarization, and antigen presentation, with relevance to MS pathogenesis. Radiologic and preliminary clinical data from a phase 2 randomized, controlled trial of temsirolimus (a rapamycin analogue) in MS show moderate efficacy, with significant adverse effects. Large clinical trials of indirect mTOR inhibitors (metformin) in MS are lacking; however, a smaller prospective, non-randomized study shows some potentially promising radiological results in combination with ex vivo beneficial effects on immune cells that might warrant further investigation. Importantly, the study of mTOR pathway contributions to autoimmune inflammatory demyelination and multiple sclerosis illustrates the difficulties in the clinical application of animal model results. Nevertheless, it is not inconceivable that targeting metabolism in the future with cell-selective mTOR inhibitors (compared to the broad inhibitors tried to date) could be developed to improve efficacy and reduce side effects.

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“…Although glucose metabolism is important for naive B cells, they also rely heavily on FAO to generate ATP [36]. During B-cell activation, FAO enables growth and proliferation [7]. Moreover, mitochondrial mass and PI3K-dependent glucose uptake is highly increased in stimulated murine B cells [36,37].…”

Section: Cytokine Signaling In B-cell Metabolismmentioning

confidence: 99%

“…In SLE, cellular metabolism is important in lymphocyte development and fate [5]. In B cells, OXPHOS, glucose metabolism, fatty acid (FA) metabolism, and the citric acid cycle (TCA) are altered in SLE [6,7].…”

Section: Introductionmentioning

confidence: 99%

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Altered Germinal-Center Metabolism in B Cells in Autoimmunity

2022

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B lymphocytes play an important role in the pathophysiology of many autoimmune disorders by producing autoantibodies, secreting cytokines, and presenting antigens. B cells undergo extreme physiological changes as they develop and differentiate. Aberrant function in tolerogenic checkpoints and the metabolic state of B cells might be the contributing factors to the dysfunctionality of autoimmune B cells. Understanding B-cell metabolism in autoimmunity is important as it can give rise to new treatments. Recent investigations have revealed that alterations in metabolism occur in the activation of B cells. Several reports have suggested that germinal center (GC) B cells of individuals with systemic lupus erythematosus (SLE) have altered metabolic function. GCs are unique microenvironments in which the delicate and complex process of B-cell affinity maturation occurs through somatic hypermutation (SHM) and class switching recombination (CSR) and where Bcl6 tightly regulates B-cell differentiation into memory B-cells or plasma cells. GC B cells rely heavily on glucose, fatty acids, and oxidative phosphorylation (OXPHOS) for their energy requirements. However, the complicated association between GC B cells and their metabolism is still not clearly understood. Here, we review several studies of B-cell metabolism, highlighting the significant transformations that occur in GC progression, and suggest possible approaches that may be investigated to more precisely target aberrant B-cell metabolism in SLE.

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B Cell Metabolism and Autophagy in Autoimmunity

Cited by 51 publications

References 145 publications

P140 Peptide Leads to Clearance of Autoreactive Lymphocytes and Normalizes Immune Response in Lupus-Prone Mice

P140 Peptide Leads to Clearance of Autoreactive Lymphocytes and Normalizes Immune Response in Lupus-Prone Mice

The mTOR Signaling Pathway in Multiple Sclerosis; from Animal Models to Human Data

Altered Germinal-Center Metabolism in B Cells in Autoimmunity

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