The activity of calcium/calmodulin-dependent protein kinase IV (CaMK4) is increased in T cells from patients with SLE and has been shown to reduce IL-2 production by promoting the effect of the transcriptional repressor cAMP responsive element modulator (CREM)-α on the IL2 promoter. Here we demonstrate that T cells from MRL/lpr mice display increased levels of CaMK4 in the nucleus and that genetic deletion of Camk4 results in improved survival. We demonstrate that absence of CaMK4 restores IL-2 production, curbs increased T cell activation, and augments the number and activity of regulatory T cells. Analogously, silencing of CaMK4 in T cells from patients with SLE increases the expression of FoxP3 upon stimulation in the presence of TGF-β. Our results demonstrate the importance of the serine/threonine kinase CaMK4 in the generation and function of regulatory T cells in patients with SLE and lupus-prone mice and its potential to serve as a therapeutic target.
Multiple elements are known to participate in ischemia reperfusion (I/R)-mediated tissue injury. Amongst them, B cells have been shown to contribute by the production of antibodies that bind to ischemic cells and fix complement. It is currently unknown whether B cells participate through antibody-independent mechanisms in the pathogenesis of I/R. In a mesenteric I/R model we found that B cells infiltrate the injured intestine of normal and autoimmune mice 2 hours after reperfusion is established. B cell depletion protected mice from the development of I/R-mediated intestinal damage. The protection conferred by B cell depletion was significantly greater in MRL/lpr mice. Finally, we show that ischemic tissue expressed the B cell-attractant CXCL13 and infiltrating B cells expressed the corresponding receptor CXCR5. Our data grants B cells an antibody-independent role in the pathogenesis of intestinal I/R and suggests that B cells accumulate in the injured tissue in response to the chemokine CXCL13.
B cell; CXCL13; inflammation; ischemia/reperfusion
Systemic lupus erythematosus (SLE) is a chronic, multi-organ inflammatory autoimmune disorder associated with high levels of circulating autoantibodies and immune complexes. We report that passive transfer of human SLE sera into mice expressing the uniquely human FcγRIIA and FcγRIIIB on neutrophils induces lupus nephritis and in some cases arthritis only when the mice additionally lack the CD18 integrin, Mac-1. The prevailing view is that Mac-1 on macrophages is responsible for immune complex clearance. However, disease permitted by the absence of Mac-1 is not related to enhanced renal immune-complex deposition or in situ C1q/C3 complement activation and proceeds even in the absence of macrophages. Instead, disease is associated with increased FcγRIIA-induced neutrophil accumulation that is enabled by Mac-1 deficiency. Intravital microscopy in the cremasteric vasculature reveals that Mac-1 mitigates FcγRIIA dependent neutrophil recruitment in response to deposited immune complexes. Our results provide direct evidence that human SLE immune-complexes are pathogenic, demonstrate that neutrophils are primary mediators of end organ damage in a novel humanized lupus mouse model, and identify Mac-1 regulation of FcγRIIA-mediated neutrophil recruitment as a key step in development of target organ damage.
T cells from patients with systemic lupus erythematosus (SLE) display increased amounts of spleen tyrosine kinase (SYK) which is involved in the aberrant CD3/T cell receptor-mediated signaling process and increased amounts of cAMP response element modulator (CREM) α which suppresses the production of interleukin-2. Because SYK expression can be suppressed by CREM α we asked why CREM α fails to suppress SYK expression in SLE T cells.
Healthy T cells were overexpressed with CREM α expression vector and SYK expression and phosphorylation was measured. A newly identified CRE site on SYK promoter was characterized by ChIP and EMSA. The CREM α-mediated repression of SYK expression was further evaluated by analyzing SYK promoter activity. T cells from SLE patients and healthy individuals were subjected to ChIP to evaluate the CREM α binding and histone-H3 acetylation.
We demonstrate that increased CREM α level can suppress SYK expression by direct binding on a CRE site of the SYK promoter in T cells from healthy individuals but failed to do so in SLE T cells. We demonstrate that failure of CREM α to suppress SYK expression in SLE T cells is due to weaker binding to the CRE site of the SYK promoter compared to healthy T cells because the promoter site is hypoacetylatylated and therefore of limited access to transcription factors.
Epigenetic alteration of the SYK promoter in SLE T cells results in inability of the transcriptional repressor CREM α to bind and suppress the expression of SYK resulting in aberrant T cell signaling.
Engagement of the CD3/T cell receptor complex in systemic lupus erythematosus (SLE) T cells involves Syk rather than the zeta-associated protein. Because Syk is being considered as a therapeutic target we asked whether Syk is central to the multiple aberrantly modulated molecules in SLE T cells. Using a gene expression array, we demonstrate that forced expression of Syk in normal T cells reproduces most of the aberrantly expressed molecules whereas silencing of Syk in SLE T cells normalizes the expression of most abnormally expressed molecules. Protein along with gene expression modulation for select molecules was confirmed. Specifically, levels of cytokine IL-21, cell surface receptor CD44, and intracellular molecules PP2A and OAS2 increased following Syk overexpression in normal T cells and decreased after Syk silencing in SLE T cells. Our results demonstrate that levels of Syk affect the expression of a number of enzymes, cytokines and receptors that play a key role in the development of disease pathogenesis in SLE and provide support for therapeutic targeting in SLE patients.
Altered T cell function in systemic lupus erythematosus (SLE) is determined by various molecular and cellular abnormalities including increased IL-17 production. Recent evidence suggests a crucial role for signaling lymphocyte activation molecules (SLAMs) in the expression of autoimmunity. In this report, we demonstrate that SLAMF3 and SLAMF6 expression is increased on the surface of SLE T cells compared to normal cells. SLAM co-engagement with CD3 under Th17 polarizing conditions results in increased IL-17 production. SLAMF3 and SLAMF6 T cell surface expression and IL-17 levels significantly correlate with disease activity in SLE patients. Both naïve and memory CD4+ T cells produce more IL-17 in response to SLAM co-stimulation as compared to CD28 co-stimulation. In naïve CD4+ cells, IL-17 production after CD28 co-stimulation peaks on day 3, whereas co-stimulation with anti-SLAMF3 and anti-SLAMF6 antibodies results in a prolonged and yet increasing production over 6 days. Unlike co-stimulation with anti-CD28, SLAM co-stimulation requires the presence of the adaptor molecule SLAM-associated protein (SAP). Thus, engagement of SLAMF3 and SLAMF6 along with antigen-mediated CD3/TCR stimulation represents an important source of IL-17 production and disruption of this interaction with decoy receptors or blocking antibodies should mitigate disease expression in SLE and other autoimmune conditions.
Renal involvement in systemic lupus erythematosus (SLE) remains a major cause of morbidity and mortality. Although immune parameters that instigate renal damage have been characterized, their link to local processes, which execute tissue damage, is poorly understood. Using genetic deletion and pharmalogical inhibition approaches we demonstrate that calcium/calmodulin-dependent protein kinase type IV (CaMKIV) which contributes to altered cytokine production in SLE patients controls spontaneous and platelet derived growth factor (PDGF)-stimulated mesangial cell proliferation and promotes IL-6 production through AP-1. Our studies identify CaMKIV as a valuable treatment target for lupus nephritis and point out the importance of local kidney factors in the expression of tissue damage which if properly targeted should enhance clinical benefit and limit toxicity.
autoimmunity; lupus nephritis; systemic lupus erythematosus; mesangial cells; CaMKIV
Systemic lupus erythematosus (SLE) is an autoimmune disease associated with chronic immune activation and tissue damage. Organ damage in SLE results from the deposition of immune complexes and the infiltration of activated T cells into susceptible organs. Cytokines are intimately involved in every step of the SLE pathogenesis. Defective immune regulation and uncontrolled lymphocyte activation, as well as increased antigen presenting cell maturation are all influenced by cytokines. Moreover, expansion of local immune responses as well as tissue infiltration by pathogenic cells is instigated by cytokines. In this review, we describe the main cytokine abnormalities reported in SLE and discuss the mechanisms that drive their aberrant production as well as the pathogenic pathways that their presence promotes.
Interleukin 23 receptor expressing IL-17 producing T cells have been shown to be important in the development of murine lupus. The usefulness of IL-23 inhibition in ameliorating lupus nephritis is unknown. We hypothesized that inhibition of IL-23 will ameliorate nephritis in lupus-prone mice. To this end, we treated MRL/lpr lupus-prone mice for 6 weeks with a rat anti-IL-23p19 antibody, which resulted in delaying the onset of nephritis without affecting the production of anti-dsDNA antibodies. The effect of the treatment was hampered by the production of murine anti-rat IgG antibodies. The amelioration of murine lupus by IL-23 inhibition strengthens the rationale for targeting IL-23 in patients with systemic lupus erythematosus.
Recent studies in cell lines and genetically engineered mice have demonstrated that cytosolic double-stranded (ds) DNA could activate dendritic cells (DCs) to become effector antigen presenting cells. Recognition of DNA might be a major factor in antimicrobial immune responses against cytosolic pathogens and also in human autoimmune diseases such as systemic lupus erythematosus. However, the role of cytosolic dsDNA in human DC activation and its effects on effector T and B cells are still elusive. Here we demonstrate that intracellular dsDNA is a potent activator of human monocyte-derived DCs, as well as primary DCs. Activation by dsDNA depends on NF-κB activation, partially on the adaptor molecule IPS-1 and the novel cytosolic dsDNA receptor IFI16, but not on the previously recognized dsDNA sentinels AIM2, DAI, RNA polymerase III or HMGBs. More importantly, we report for the first time that human dsDNA-activated DCs, rather than LPS- or inflammatory cytokine cocktail-activated DCs, represent the most potent inducers of naïve CD4+ T cells to promote Th1-type cytokine production and to generate CD4+ and CD8+ cytotoxic T cells. dsDNA-, but not LPS- or cocktail-activated DCs induce B cells to produce complement fixing IgG1 and IgG3 antibodies. We propose that cytosolic dsDNA represents a novel, more effective approach to generate DCs to enhance vaccine effectiveness in reprogramming the adaptive immune system to eradicate infectious agents, autoimmunity, allergy and cancer.
T cells from patients with systemic lupus erythematosus exhibit a notable array of defects that probably contribute to the origin and development of the disease. Such abnormalities include an abnormal response to stimulation, aberrant expression of molecules that play key roles in intracellular signalling pathways, altered transcription factor activation and binding, and skewed gene expression. The combination of these alterations leads the cell to the expression of a particular phenotype that intense research has gradually uncovered over the last years. The aim of this article is to review the findings that have allowed us to better understand the behaviour of the lupus T cell and highlight the molecules that represent potential therapeutic targets.
Epstein-Barr virus (EBV) attachment to primary B-cells initiates virus entry. While CD21 is the only known receptor for EBVgp350/220 a recent report documents EBV infects B-cells from a patient genetically deficient in CD21. On normal resting B-cells CD21 forms two membrane complexes, one with CD19 another with CD35. Whereas the CD21/CD19 complex is widely retained on immortalized and B-cell tumor lines, the related complement-regulatory protein CD35 is lost. To determine the role(s) of CD35 in initial infection, we transduced a CD21-negative pre-B-cell and myeloid leukemia line with CD35, CD21 or both. Cells expressing CD35 alone bound gp350/220 and became latently infected when the fusion receptor HLA II was co-expressed. Temporal, biophysical and structural characteristics of CD35-mediated infection were distinct from CD21. Identification of CD35 as an EBV receptor uncovers a salient role in primary infection, addresses unsettled questions of virus tropism, and underscores the importance of EBVgp350/220 for vaccine development.
The contribution of individual molecular aberrations to the pathogenesis of systemic lupus erythematosus (SLE), an autoimmune disease that affects multiple organs, is often difficult to evaluate because of the presence of abundant confounding factors. To assess the effect of increased expression of the phosphatase PP2A in T cells, as recorded in SLE patients, we generated a transgenic mouse that overexpresses the PP2Ac subunit in T cells. The transgenic mouse displays a heightened susceptibility to immune-mediated glomerulonephritis in the absence of other immune defects. CD4+ T cells produce increased amounts of IL-17 while the number of neutrophils in the peripheral blood is increased. IL-17 neutralization abrogated the development of glomerulonephritis. We conclude that increased PP2Ac expression participates in SLE pathogenesis by promoting inflammation through unchecked IL-17 production and facilitating the development of end-organ damage.
The catalytic subunit α isoform of protein phosphatase 2A (PP2Acα) activity, protein, and mRNA have been found increased in systemic lupus erythematosus (SLE) T cells and to contribute to decreased IL-2 production. The PP2Acα promoter activity is controlled epigenetically through the methylation of a CpG within a cAMP response element (CRE) motif defined by its promoter. We considered that hypomethylation may account for the increased expression of PP2Acα in patients with SLE. Using bisulfite sequencing, we found that SLE T cells displayed decreased DNA methylation in the promoter region compared with normal T cells. More importantly, we found that the CRE-defined CpG, which binds p-CREB, is significantly less methylated in SLE compared with normal T cells, and the levels of methylation correlated with decreased amounts of DNA methyltransferase 1 transcripts. Methylation intensity correlated inversely with levels of PP2Acα mRNA and SLE disease activity. Chromatin immunoprecipitation assays revealed more binding of p-CREB to the CRE site in SLE T cells, resulting in increased expression of PP2Acα. We propose that PP2Acα represents a new methylation-sensitive gene that, like the previously reported CD70 and CD11a, contributes to the pathogenesis of SLE.
Systemic lupus erythematousus (SLE) is a chronic inflammatory disease associated with aberrant immune cell function. Treatment involves the use of indiscriminate immunosuppression with significant side effects. SLE T cells express high levels of calcium/calmodulin-dependent protein kinase type IV (CaMKIV) which translocates to the nucleus upon engagement of the T cell receptor (TCR)/CD3 and accounts for abnormal T cell function. We hypothesized that inhibition of CaMKIV should improve disease pathology.
We treated MRL/lpr mice with KN-93, a CaMKIV inhibitor, starting either at week 8 or week 12 of age through week 16 and evaluated skin lesions, proteinuria, kidney histopathology, pro-inflammatory cytokine production and co-stimulatory molecule expression. We also determined the effect of silencing of CaMKIV on IFN-γ expression by human SLE T cells.
We report that CaMKIV inhibition in MRL/lpr mice results in significant suppression of nephritis, skin disease, decreased expression of the co-stimulatory molecules CD86 and CD80 on B cells and suppression of IFN-γ and TNF-α production. In human SLE T cells, silencing of CaMKIV resulted in suppression of IFN-γ production.
We conclude that suppression of CaMKIV mitigates disease development in lupus-prone mice by suppressing cytokine production and co-stimulatory molecule expression. Specific silencing of CaMKIV in human T cells results in similar suppression of IFN-γ production. Our data justify the development of small molecule CaMKIV inhibitors for the treatment of patients with SLE.
Recent evidence suggests that systemic autoimmunity and immunodeficiency are not separate entities, but rather interconnected processes. Immunodeficiency results from distinct defects of the immune response and primarily presents as infections, but also frequently with autoimmune features. Systemic autoimmunity is the combined effect of multiple genetic variations, infectious and immunoregulatory factors that result in dominant autoimmune manifestations in addition to frequent and opportunistic infections. The overlap in disease manifestations and symptoms suggests that immunodeficiency should be considered in the presence of autoimmunity, and vice versa. In this review, we present the shared or similar aspects of immunodeficiency and autoimmunity using systemic lupus erythematosus as a paradigm and discuss the implications for clinical care.
Skin disease is the second most common manifestation in patients with systemic lupus erythematosus (SLE). TNF receptor (TNFR) preligand assembly domain (PLAD) has been found to block the effect of TNF-α and TNFR1 PLAD (P60 PLAD) inhibits inflammatory arthritis. We asked whether TNFR PLAD can limit inflammatory skin injury in SLE.
Female MRL/lpr mice received P60 PLAD (100 µg/mouse, i.p.) or P80 PLAD (100 µg/mouse, i.p.) or PBS (100 µl/mouse, i.p.) three times a week starting at age of 6 weeks for 26 weeks.
Immunohistochemistry studies demonstrated that TNFR1 but not TNFR2 is dominantly expressed in skin lesions in MRL/lpr mice. We found that TNFR1 PLAD but not TNFR2 PLAD (P80 PLAD) protein significantly inhibited skin injury in lupus MRL/lpr mice. P60 PLAD significantly inhibited NF-κB, MCP-1 and iNOS expression in skin lesions. P60 PLAD reduced lupus serum-induced monocyte differentiation into dendritic cells. P60 PLAD did not reduce IgG deposition in the skin and improve kidney pathology progression in MRL/lpr mice.
Our results indicate that TNFR1 is involved in the expression of skin injury in lupus MRL/lpr mice and P60 PLAD or similar biologics may be of clinical value if applied locally.
Experimental autoimmune orchitis (EAO), the principal model of non-infectious testicular inflammatory disease, can be induced in susceptible mouse strains by immunization with autologous testicular homogenate and appropriate adjuvants. As previously established, the genome of DBA/2J mice encodes genes that are capable of conferring dominant resistance to EAO, while the genome of BALB/cByJ mice does not and they are therefore susceptible to EAO. In a genome scan, we previously identified Orch3 as the major quantitative trait locus controlling dominant resistance to EAO and mapped it to chromosome 11. Here, by utilizing a forward genetic approach, we identified kinesin family member 1C (Kif1c) as a positional candidate for Orch3 and, using a transgenic approach, demonstrated that Kif1c is Orch3. Mechanistically, we showed that the resistant Kif1cD2 allele leads to a reduced antigen-specific T cell proliferative response as a consequence of decreased MHC class II expression by antigen presenting cells, and that the L578→P578 and S1027→P1027 polymorphisms distinguishing the BALB/cByJ and DBA/2J alleles, respectively, can play a role in transcriptional regulation. These findings may provide mechanistic insight into how polymorphism in other kinesins such as KIF21B and KIF5A influence susceptibility and resistance to human autoimmune diseases.
Although the etiology of autoimmunity is not well known, a variety of studies have demonstrated that genetic predisposition is a major contributor to disease susceptibility and resistance. The major histocompatibility complex (MHC) is the primary genetic determinant of autoimmune disease susceptibility with multiple additional interacting loci required. However, the identification and characterization of non–MHC genes has been problematic, since most autoimmune diseases are polygenic with the individual genes exhibiting only partial or minimal penetrance. We previously identified Orch3 (mouse chromosome 11) as the most important immune-suppressive locus controlling dominant resistance to autoimmune orchitis, the principal animal model of non-infectious testicular inflammatory/autoimmune disease. Here, using congenic mapping, we identified kinesin family member 1C (Kif1c) as a positional candidate for Orch3. Furthermore, over-expression of the Kif1c resistant allele in susceptible mice rendered animals autoimmune orchitis resistant, demonstrating that Kif1c is Orch3. We propose that Kif1c plays an immunoregulatory role by controlling the levels of MHC class II in antigen presenting cells and consequently impacting autoreactive orchitogenic T cell responses. These finding are particularly relevant since polymorphism in other kinesins such as KIF21B and KIF5A have been associated with susceptibility and resistance to human autoimmune disease.
The pathogenic origin of autoimmune diseases can be traced to both genetic susceptibility and epigenetic modifications arising from exposure to the environment. Epigenetic modifications influence gene-expression and alter cellular functions without modifying the genomic sequence. CpG-DNA methylation, histone-tail modifications, and micro-RNAs (miRNAs) are the main epigenetic mechanisms of gene regulation. Understanding the molecular mechanisms that are involved in the pathophysiology of autoimmune diseases is essential for the introduction of effective, target-directed, and tolerated therapies. In this review, we summarize recent findings that signify the importance of epigenetic modifications in autoimmune disorders while focusing on systemic lupus erythematosus (SLE). We discuss future directions in basic research, autoimmune diagnostics, and applied therapy.
Systemic lupus erythematosus (SLE) is an autoimmune disease that predominantly affects women and presents with manifestations derived from the involvement of multiple organs including the kidneys, joints, nervous system, and hematopoietic organs. Immune system aberrations, as well as heritable, hormonal, and environmental factors interplay in the expression of organ damage. Recent contributions from different fields have developed our understanding of SLE and reshaped current pathogenic models. Here, we review novel information that deals with 1) genes associated with disease expression, 2) immune cell molecular abnormalities that lead to autoimmune pathology, 3) the role of hormones and sex chromosomes in the development of disease, 4) environmental and epigenetic factors thought to contribute to the expression of SLE. Finally, we emphasize molecular defects intimately associated with the disease process of SLE that represent ideal therapeutic targets and disease biomarkers.
T cells that express IL-17 infiltrate the kidneys of patients with systemic lupus erythematosus. A significant proportion of these cells are CD3+CD4−CD8− double-negative T cells. In this study, we show that double-negative T cells from MRL/lpr mice express high amounts of IL-17 and that as disease progressively worsens, the expression of IL-17 and of IL-23 receptor in lymphocytes from these mice increases. Lymph node cells from lupus-prone mice, but not control mice, treated in vitro with IL-23 induce nephritis when transferred to non-autoimmune, lymphocyte-deficient Rag-1−/− mice. Kidney specimens from these recipient mice show significant Ig and complement deposition. The data indicate that an aberrantly active IL-23/IL-17 axis contributes to the development of nephritis in lupus-prone mice.
The origin and function of human double negative (DN) TCR-αβ+ T cells is unknown. They are thought to contribute to the pathogenesis of systemic lupus erythematosus because they expand and accumulate in inflamed organs. In this study, we provide evidence that human TCR-αβ+ CD4− CD8− DN T cells can derive from activated CD8+ T cells. Freshly isolated TCR-αβ+ DN T cells display a distinct gene expression and cytokine production profile. DN cells isolated from peripheral blood as well as DN cells derived in vitro from CD8+ T cells produce a defined array of proinflammatory mediators that includes IL-1β, IL-17, IFN-γ, CXCL3, and CXCL2. These results indicate that, upon activation, CD8+ T cells have the capacity to acquire a distinct phenotype that grants them inflammatory capacity.
Spleen tyrosine kinase (Syk) is involved in membrane-mediated signaling in various cells, including immune cells. It is overexpressed in T cells from patients with systemic lupus erythematosus (SLE), and its inhibition has been shown to improve T cell function as well as to improve disease manifestations in (NZB × NZW)F1 lupus-prone mice and in patients with rheumatoid arthritis. While clinical trials examining Syk inhibition in patients with SLE are being considered, the aim of our experiments was to determine whether the therapeutic effects of Syk inhibition extend to other strains of lupus-prone mice and whether they result in improvement in skin disease and modification of established disease.
Female MRL/lpr or BAK/BAX mice were studied. Starting either at age 4 weeks (before disease) or at age 16 weeks (after established disease) and continuing for up to 16 weeks, mice were fed chow containing the Syk inhibitor R788 or control chow.
We found that inhibition of Syk in MRL/lpr and BAK/BAX mice prevented the development of skin disease and significantly reduced established skin disease. Similarly, Syk inhibition reduced the size of the spleen and lymph nodes, suppressed the development of renal disease, and suppressed established renal disease. Discontinuation of treatment resulted in extended suppression of skin disease for at least 8 weeks and suppression of renal disease for 4 weeks.
Syk inhibition suppresses the development of lupus skin and kidney disease in lupus-prone mice, suppresses established disease in lupus-prone mice, and may represent a valuable treatment for patients with SLE.
Purpose of review
Over the past year several key pathways in systemic lupus erythematosus (SLE) lymphocyte signaling have been identified. Pathways that can be exploited for therapy are discussed in this review.
Inhibition of SLE T cell activation by blocking spleen tyrosine kinase (Syk) and SLE T cell migration by blocking CD44 or CXCR4 lead to amelioration of lupus in lupus-prone mice. Similar results can be achieved by boosting CD8+ Treg numbers. Small molecules that block the kinases CaMKIV (calcium and calmodulin dependent kinase IV) and Bruton Tyrosine kinase (Btk) and the phosphatase calcineurin were shown to be effective in treating murine lupus. Finally, gene methylation status determines the expression of several key genes in SLE and strategies to correct it have shown promising results in preclinical studies.
Molecules that enhance T cell receptor (TCR) signaling or increase lymphocyte migration can be inhibited successfully with significant improvement of disease intensity in lupus-prone mice using small molecules. Manipulation of promoter methylation and histone acetylation represents a novel way to alter gene transcription in SLE.
epigenetics; lymphocytes; systemic lupus erythematosus (SLE); treatment
IL-17 is a cytokine with powerful proinflammatory activity. Production of IL-17 is abnormally increased in patients with systemic lupus erythematosus (SLE), a multiorgan chronic autoimmune disease. In patients with SLE, CD3+CD4−CD8− (double negative) T cells are an important source of IL-17. IL-17 produced by double negative and CD4 T cells participates in the pathogenesis of the disease. IL-17-producing T cells are present in the kidneys of patients with lupus nephritis. IL-17 increased production in patients with SLE can amplify the immune response by increasing target organ inflammation and damage and by augmenting the production of antibodies by B cells.