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1.
Nat Immunol ; 2024 Jul 15.
Article in English | MEDLINE | ID: mdl-39009839

ABSTRACT

Understanding the pathogenesis and clinical manifestations of systemic lupus erythematosus (SLE) has been a great challenge. Reductionist approaches to understand the nature of the disease have identified many pathogenetic contributors that parallel clinical heterogeneity. This Review outlines the immunological control of SLE and looks to experimental tools and approaches that are improving our understanding of the complex contribution of interacting genetics, environment, sex and immunoregulatory factors and their interface with processes inherent to tissue parenchymal cells. Efforts to advance precision medicine in the care of patients with SLE along with treatment strategies to correct the immune system hold hope and are also examined.

2.
Sci Adv ; 10(27): eado2365, 2024 Jul 05.
Article in English | MEDLINE | ID: mdl-38959302

ABSTRACT

Pityriasis rubra pilaris (PRP) is a rare inflammatory skin disease with a poorly understood pathogenesis. Through a molecularly driven precision medicine approach and an extensive mechanistic pathway analysis in PRP skin samples, compared to psoriasis, atopic dermatitis, healed PRP, and healthy controls, we identified IL-1ß as a key mediator, orchestrating an NF-κB-mediated IL-1ß-CCL20 axis, including activation of CARD14 and NOD2. Treatment of three patients with the IL-1 antagonists anakinra and canakinumab resulted in rapid clinical improvement and reversal of the PRP-associated molecular signature with a 50% improvement in skin lesions after 2 to 3 weeks. This transcriptional signature was consistent with in vitro stimulation of keratinocytes with IL-1ß. With the central role of IL-1ß underscoring its potential as a therapeutic target, our findings propose a redefinition of PRP as an autoinflammatory keratinization disorder. Further clinical trials are needed to validate the efficacy of IL-1ß antagonists in PRP.


Subject(s)
Antibodies, Monoclonal, Humanized , Interleukin 1 Receptor Antagonist Protein , Interleukin-1beta , Keratinocytes , Pityriasis Rubra Pilaris , Humans , Pityriasis Rubra Pilaris/drug therapy , Pityriasis Rubra Pilaris/pathology , Pityriasis Rubra Pilaris/genetics , Interleukin-1beta/metabolism , Interleukin-1beta/antagonists & inhibitors , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Keratinocytes/metabolism , Keratinocytes/drug effects , Keratinocytes/pathology , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/pharmacology , Male , NF-kappa B/metabolism , Nod2 Signaling Adaptor Protein/metabolism , Nod2 Signaling Adaptor Protein/genetics , Nod2 Signaling Adaptor Protein/antagonists & inhibitors , Female , CARD Signaling Adaptor Proteins/metabolism , CARD Signaling Adaptor Proteins/genetics , Skin/pathology , Skin/metabolism , Skin/drug effects , Interleukin-1/antagonists & inhibitors , Interleukin-1/metabolism , Interleukin-1/genetics , Middle Aged , Guanylate Cyclase/metabolism , Guanylate Cyclase/antagonists & inhibitors , Guanylate Cyclase/genetics , Adult , Signal Transduction/drug effects , Membrane Proteins
3.
Eur J Immunol ; : e2451274, 2024 Jul 19.
Article in English | MEDLINE | ID: mdl-39031517

ABSTRACT

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with multifaceted pathogenetic processes, including abnormalities of T-cell subset distribution and function. Accumulation of senescent CD4+ T cells has been found to contribute to the development of the disease. In this issue, Jiang et al. provide compelling evidence that links an expanded pool of CD4+CD57+ senescent T cells in patients with SLE to disease activity favored by interleukin-15. Importantly, treatment of lupus-prone mice with a senolytic drug resulted in decreased autoimmune pathology. The findings of this study suggest possible novel therapeutics to treat patients with SLE.

4.
Cell Rep ; 43(7): 114379, 2024 Jun 17.
Article in English | MEDLINE | ID: mdl-38889006

ABSTRACT

The protein phosphatase 2A (PP2A) regulatory subunit PPP2R2A is involved in the regulation of immune response. We report that lupus-prone mice with T cells deficient in PPP2R2A display less autoimmunity and nephritis. PPP2R2A deficiency promotes NAD+ biosynthesis through the nicotinamide riboside (NR)-directed salvage pathway in T cells. NR inhibits murine Th17 and promotes Treg cell differentiation, in vitro, by PΑRylating histone H1.2 and causing its reduced occupancy in the Foxp3 loci and increased occupancy in the Il17a loci, leading to increased Foxp3 and decreased Il17a transcription. NR treatment suppresses disease in MRL.lpr mice and restores NAD+-dependent poly [ADP-ribose] polymerase 1 (PARP1) activity in CD4 T cells from patients with systemic lupus erythematosus (SLE), while reducing interferon (IFN)-γ and interleukin (IL)-17 production. We conclude that PPP2R2A controls the level of NAD+ through the NR-directed salvage pathway and promotes systemic autoimmunity. Translationally, NR suppresses lupus nephritis in mice and limits the production of proinflammatory cytokines by SLE T cells.

5.
Nat Commun ; 15(1): 2194, 2024 Mar 11.
Article in English | MEDLINE | ID: mdl-38467629

ABSTRACT

The regulation of thymocyte development by RNA-binding proteins (RBPs) is largely unexplored. We identify 642 RBPs in the thymus and focus on Arpp21, which shows selective and dynamic expression in early thymocytes. Arpp21 is downregulated in response to T cell receptor (TCR) and Ca2+ signals. Downregulation requires Stim1/Stim2 and CaMK4 expression and involves Arpp21 protein phosphorylation, polyubiquitination and proteasomal degradation. Arpp21 directly binds RNA through its R3H domain, with a preference for uridine-rich motifs, promoting the expression of target mRNAs. Analysis of the Arpp21-bound transcriptome reveals strong interactions with the Rag1 3'-UTR. Arpp21-deficient thymocytes show reduced Rag1 expression, delayed TCR rearrangement and a less diverse TCR repertoire. This phenotype is recapitulated in Rag1 3'-UTR mutant mice harboring a deletion of the Arpp21 response region. These findings show how thymocyte-specific Arpp21 promotes Rag1 expression to enable TCR repertoire diversity until signals from the TCR terminate Arpp21 and Rag1 activities.


Subject(s)
Receptors, Antigen, T-Cell , Thymocytes , Animals , Mice , Cell Differentiation/genetics , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Thymocytes/metabolism , Thymus Gland/metabolism
6.
J Autoimmun ; 143: 103167, 2024 02.
Article in English | MEDLINE | ID: mdl-38301504

ABSTRACT

IL-23-activation of IL-17 producing T cells is involved in many rheumatic diseases. Herein, we investigate the role of IL-23 in the activation of myeloid cell subsets that contribute to skin inflammation in mice and man. IL-23 gene transfer in WT, IL-23RGFP reporter mice and subsequent analysis with spectral cytometry show that IL-23 regulates early innate immune events by inducing the expansion of a myeloid MDL1+CD11b+Ly6G+ population that dictates epidermal hyperplasia, acanthosis, and parakeratosis; hallmark pathologic features of psoriasis. Genetic ablation of MDL-1, a major PU.1 transcriptional target during myeloid differentiation exclusively expressed in myeloid cells, completely prevents IL-23-pathology. Moreover, we show that IL-23-induced myeloid subsets are also capable of producing IL-17A and IL-23R+MDL1+ cells are present in the involved skin of psoriasis patients and gene expression correlations between IL-23 and MDL-1 have been validated in multiple patient cohorts. Collectively, our data demonstrate a novel role of IL-23 in MDL-1-myelopoiesis that is responsible for skin inflammation and related pathologies. Our data open a new avenue of investigations regarding the role of IL-23 in the activation of myeloid immunoreceptors and their role in autoimmunity.


Subject(s)
Arthritis, Psoriatic , Dermatitis , Psoriasis , Humans , Arthritis, Psoriatic/pathology , Interleukin-17/genetics , Interleukin-17/metabolism , Neutrophils/metabolism , Skin/pathology , Dermatitis/pathology , Inflammation , Interleukin-23/genetics , Interleukin-23/metabolism , Receptors, Cell Surface/metabolism , Lectins, C-Type/genetics
7.
Nat Commun ; 15(1): 840, 2024 Jan 29.
Article in English | MEDLINE | ID: mdl-38287012

ABSTRACT

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by dysregulated B cell compartment responsible for the production of autoantibodies. Here, we show that T cell-specific expression of calcium/calmodulin-dependent protein kinase IV (CaMK4) leads to T follicular helper (Tfh) cells expansion in models of T-dependent immunization and autoimmunity. Mechanistically, CaMK4 controls the Tfh-specific transcription factor B cell lymphoma 6 (Bcl6) at the transcriptional level through the cAMP responsive element modulator α (CREMα). In the absence of CaMK4 in T cells, germinal center formation and humoral immunity is impaired in immunized mice, resulting in reduced anti-dsDNA titres, as well as IgG and complement kidney deposition in the lupus-prone B6.lpr mouse. In human Tfh cells, CaMK4 inhibition reduced BCL6 expression and IL-21 secretion ex vivo, resulting in impaired plasmablast formation and IgG production. In patients with SLE, CAMK4 mRNA levels in Tfh cells correlated with those of BCL6. In conclusion, we identify CaMK4/CREMα as a driver of T cell-dependent B cell dysregulation in autoimmunity.


Subject(s)
Lupus Erythematosus, Systemic , T Follicular Helper Cells , Animals , Humans , Mice , Autoimmunity , Cell Differentiation/genetics , Immunoglobulin G/metabolism , T Follicular Helper Cells/metabolism , T-Lymphocytes, Helper-Inducer
8.
Int J Mol Sci ; 25(2)2024 Jan 09.
Article in English | MEDLINE | ID: mdl-38255879

ABSTRACT

Lupus nephritis (LN), a major complication in individuals diagnosed with systemic lupus erythematosus, substantially increases morbidity and mortality. Despite marked improvements in the survival of patients with severe LN over the past 50 years, complete clinical remission after immunosuppressive therapy is achieved in only half of the patients. Therefore, timely detection of LN is vital for initiating prompt therapeutic interventions and improving patient outcomes. Biomarkers have emerged as valuable tools for LN detection and monitoring; however, the complex role of these biomarkers in LN pathogenesis remains unclear. Renal biopsy remains the gold standard for the identification of the histological phenotypes of LN and guides disease management. However, the molecular pathophysiology of specific renal lesions remains poorly understood. In this review, we provide a critical, up-to-date overview of the latest developments in the field of LN biomarkers.


Subject(s)
Lupus Erythematosus, Systemic , Lupus Nephritis , Humans , Lupus Nephritis/diagnosis , Biomarkers , Kidney , Phenotype , Pathologic Complete Response
9.
Nat Rev Nephrol ; 20(4): 206-217, 2024 Apr.
Article in English | MEDLINE | ID: mdl-37985868

ABSTRACT

The deposition of immune complexes, activation of complement and infiltration of the kidney by cells of the adaptive and innate immune systems have long been considered responsible for the induction of kidney damage in autoimmune, alloimmune and other inflammatory kidney diseases. However, emerging findings have highlighted the contribution of resident immune cells and of immune molecules expressed by kidney-resident parenchymal cells to disease processes. Several types of kidney parenchymal cells seem to express a variety of immune molecules with a distinct topographic distribution, which may reflect the exposure of these cells to different pathogenic threats or microenvironments. A growing body of literature suggests that these cells can stimulate the infiltration of immune cells that provide protection against infections or contribute to inflammation - a process that is also regulated by draining kidney lymph nodes. Moreover, components of the immune system, such as autoantibodies, cytokines and immune cells, can influence the metabolic profile of kidney parenchymal cells in the kidney, highlighting the importance of crosstalk in pathogenic processes. The development of targeted nanomedicine approaches that modulate the immune response or control inflammation and damage directly within the kidney has the potential to eliminate the need for systemically acting drugs.


Subject(s)
Cytokines , Kidney , Humans , Immunity, Innate , Inflammation , Autoantibodies
11.
Eur J Rheumatol ; 10(4): 148-158, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37850609

ABSTRACT

Patients with systemic lupus erythematosus experience high rates of infections. The use of immunosuppressive drugs to treat the disease, along with the fact that both the innate and adaptive branches of the immune system are compromised, account for the development of infections. In this communication, we briefly discuss the aberrant function of the immune system in patients with systemic lupus erythematosus and review the occurrence of infections that have been reported in clinical trials conducted to develop new therapeutics. Understanding the immune dysfunction in patients with systemic lupus erythematosus and the appearance of infections while trying to control the disease using immunosuppressive or immunomodulatory drugs should help limit infections and mitigate the associated morbidity and mortality.

12.
Cell Mol Immunol ; 20(11): 1339-1351, 2023 11.
Article in English | MEDLINE | ID: mdl-37737309

ABSTRACT

Inhibitory immune receptors set thresholds for immune cell activation, and their deficiency predisposes a person to autoimmune responses. However, the agonists of inhibitory immune receptors remain largely unknown, representing untapped sources of treatments for autoimmune diseases. Here, we show that V-set and transmembrane domain-containing 1 (VSTM1) is an inhibitory receptor and that its binding by the competent ligand soluble galectin-1 (Gal1) is essential for maintaining neutrophil viability mediated by downregulated reactive oxygen species production. However, in patients with systemic lupus erythematosus (SLE), circulating Gal1 is oxidized and cannot be recognized by VSTM1, leading to increased intracellular reactive oxygen species levels and reduced neutrophil viability. Dysregulated neutrophil function or death contributes significantly to the pathogenesis of SLE by providing danger molecules and autoantigens that drive the production of inflammatory cytokines and the activation of autoreactive lymphocytes. Interestingly, serum levels of glutathione, an antioxidant able to convert oxidized Gal1 to its reduced form, were negatively correlated with SLE disease activity. Taken together, our findings reveal failed inhibitory Gal1/VSTM1 pathway activation in patients with SLE and provide important insights for the development of effective targeted therapies.


Subject(s)
Lupus Erythematosus, Systemic , Neutrophils , Humans , Galectin 1 , Reactive Oxygen Species/metabolism
13.
Adv Mater ; 35(40): e2300812, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37357903

ABSTRACT

Immune therapeutics holds great promise in the treatment of type 1 diabetes (T1D). Nonetheless, their progress is hampered by limited efficacy, equipoise, or issues of safety. To address this, a novel and specific nanodelivery platform for T1D that targets high endothelial venules (HEVs) presented in the pancreatic lymph nodes (PLNs) and pancreas is developed. Data indicate that the pancreata of nonobese diabetic (NOD) mice and patients with T1D are unique in their expression of newly formed HEVs. Anti-CD3 mAb is encapsulated in poly(lactic-co-glycolic acid)-poly(ethylene glycol) nanoparticles (NPs), the surfaces of which are conjugated with MECA79 mAb that recognizes HEVs. Targeted delivery of these NPs improves accumulation of anti-CD3 mAb in both the PLNs and pancreata of NOD mice. Treatment of hyperglycemic NOD mice with MECA79-anti-CD3-NPs results in significant reversal of T1D compared to those that are untreated, treated with empty NPs, or provided free anti-CD3. This effect is associated with a significant reduction of T effector cell populations in the PLNs and a decreased production of pro-inflammatory cytokine in the mice treated with MECA79-anti-CD3-NPs. In summary, HEV-targeted therapeutics may be used as a means by which immune therapeutics can be delivered to PLNs and pancreata to suppress autoimmune diabetes effectively.


Subject(s)
Diabetes Mellitus, Type 1 , Humans , Mice , Animals , Diabetes Mellitus, Type 1/drug therapy , Mice, Inbred NOD , Pancreas
14.
Cell Metab ; 35(5): 728-729, 2023 05 02.
Article in English | MEDLINE | ID: mdl-37137285

ABSTRACT

Immune cell microenvironment plays a major role in the aberrant function of immune cells in systemic lupus erythematosus. Zeng and co-authors show that in human and murine lupus, splenic stromal cell-derived acetylcholine switches B cell metabolism to fatty acid oxidation and promotes B cell autoreactivity and disease development.


Subject(s)
Autoimmunity , Lupus Erythematosus, Systemic , Mice , Humans , Animals , Lupus Erythematosus, Systemic/metabolism , B-Lymphocytes/metabolism , Neurotransmitter Agents/metabolism
17.
Clin Immunol ; 248: 109264, 2023 03.
Article in English | MEDLINE | ID: mdl-36804225

ABSTRACT

Autoimmune manifestations were reported in people infected with SARS-CoV-2. Repetitive exposure of mice to foreign antigen may lead to the onset of autoimmunity. We therefore investigated whether repetitive exposure to the SARS-CoV-2 spike protein could result in autoimmunity. To address this hypothesis, we repeatedly immunized C57Bl/6 mice with spike protein injected intraperitoneally. At the end of the immunization, mice which received spike protein produced anti-spike IgG but none of them developed anti-dsDNA antibodies or proteinuria. In conclusion, repetitive immunization with SARS-CoV-2 spike protein does not induce autoimmunity in the present mice model. Albeit reassuring, these results need to be confirmed by large epidemiological study evaluating the incidence of autoimmune diseases in individuals with repetitive SARS-CoV-2 antigen exposure.


Subject(s)
Autoimmune Diseases , COVID-19 , Animals , Humans , Mice , Autoimmunity , Spike Glycoprotein, Coronavirus , SARS-CoV-2 , Mice, Inbred C57BL , Antibodies, Viral
18.
Nat Rev Immunol ; 23(8): 495-510, 2023 08.
Article in English | MEDLINE | ID: mdl-36707719

ABSTRACT

Immune-mediated inflammatory diseases (IMIDs) are characterized by excessive and uncontrolled inflammation and thrombosis, both of which are responsible for organ damage, morbidity and death. Platelets have long been known for their role in primary haemostasis, but they are now also considered to be components of the immune system and to have a central role in the pathogenesis of IMIDs. In patients with IMIDs, platelets are activated by disease-specific factors, and their activation often reflects disease activity. Here we summarize the evidence showing that activated platelets have an active role in the pathogenesis and the progression of IMIDs. Activated platelets produce soluble factors and directly interact with immune cells, thereby promoting an inflammatory phenotype. Furthermore, platelets participate in tissue injury and promote abnormal tissue healing, leading to fibrosis. Targeting platelet activation and targeting the interaction of platelets with the immune system are novel and promising therapeutic strategies in IMIDs.


Subject(s)
Blood Platelets , Thrombosis , Humans , Immunomodulating Agents , Platelet Activation , Inflammation
19.
Rheumatology (Oxford) ; 62(2): 861-871, 2023 02 01.
Article in English | MEDLINE | ID: mdl-35781320

ABSTRACT

OBJECTIVE: To investigate the role of calcium/calmodulin-dependent protein kinase IV (CaMK4) in the development of joint injury in a mouse model of arthritis and patients with RA. METHODS: Camk4-deficient, Camk4flox/floxLck-Cre, and mice treated with CaMK4 inhibitor KN-93 or KN-93 encapsulated in nanoparticles tagged with CD4 or CD8 antibodies were subjected to collagen-induced arthritis (CIA). Inflammatory cytokine levels, humoral immune response, synovitis, and T-cell activation were recorded. CAMK4 gene expression was measured in CD4+ T cells from healthy participants and patients with active RA. Micro-CT and histology were used to assess joint pathology. CD4+ and CD14+ cells in patients with RA were subjected to Th17 or osteoclast differentiation, respectively. RESULTS: CaMK4-deficient mice subjected to CIA displayed improved clinical scores and decreased numbers of Th17 cells. KN-93 treatment significantly reduced joint destruction by decreasing the production of inflammatory cytokines. Furthermore, Camk4flox/floxLck-Cre mice and mice treated with KN93-loaded CD4 antibody-tagged nanoparticles developed fewer Th17 cells and less severe arthritis. CaMK4 inhibition mitigated IL-17 production by CD4+ cells in patients with RA. The number of in vitro differentiated osteoclasts from CD14+ cells in patients with RA was significantly decreased with CaMK4 inhibitors. CONCLUSION: Using global and CD4-cell-targeted pharmacologic approaches and conditionally deficient mice, we demonstrate that CaMK4 is important in the development of arthritis. Using ex vivo cell cultures from patients with RA, CaMK4 is important for both Th17 generation and osteoclastogenesis. We propose that CaMK4 inhibition represents a new approach to control the development of arthritis.


Subject(s)
Arthritis, Experimental , Osteogenesis , Animals , Mice , Calcium-Calmodulin-Dependent Protein Kinase Type 4/metabolism , Calcium/therapeutic use , Th17 Cells , Cytokines/metabolism , Arthritis, Experimental/metabolism , Cell Differentiation
20.
Curr Opin Rheumatol ; 35(2): 107-116, 2023 03 01.
Article in English | MEDLINE | ID: mdl-35797522

ABSTRACT

PURPOSE OF REVIEW: Lupus nephritis is associated with significant mortality and morbidity. We lack effective therapeutics and biomarkers mostly because of our limited understanding of its complex pathogenesis. We aim to present an overview of the recent advances in the field to gain a deeper understanding of the underlying cellular and molecular mechanisms involved in lupus nephritis pathogenesis. RECENT FINDINGS: Recent studies have identified distinct roles for each resident kidney cell in the pathogenesis of lupus nephritis. Podocytes share many elements of innate and adaptive immune cells and they can present antigens and participate in the formation of crescents in coordination with parietal epithelial cells. Mesangial cells produce pro-inflammatory cytokines and secrete extracellular matrix contributing to glomerular fibrosis. Tubular epithelial cells modulate the milieu of the interstitium to promote T cell infiltration and formation of tertiary lymphoid organs. Modulation of specific genes in kidney resident cells can ward off the effectors of the autoimmune response including autoantibodies, cytokines and immune cells. SUMMARY: The development of lupus nephritis is multifactorial involving genetic susceptibility, environmental triggers and systemic inflammation. However, the role of resident kidney cells in the development of lupus nephritis is becoming more defined and distinct. More recent studies point to the restoration of kidney resident cell function using cell targeted approaches to prevent and treat lupus nephritis.


Subject(s)
Lupus Nephritis , Podocytes , Humans , Lupus Nephritis/etiology , Kidney/pathology , Epithelial Cells/pathology , Cytokines
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