Autoantibodies to Killer Cell Immunoglobulin-Like Receptors in Patients With Systemic Lupus Erythematosus Induce Natural Killer Cell Hyporesponsiveness

Abstract

Natural killer (NK) cell cytotoxicity toward self-cells is restrained by the inhibitory HLA class I-binding receptors CD94/NKG2A and the killer cell immunoglobulin-like receptors (KIRs). CD94/NKG2A and KIRs are also essential for NK cell education, which is a dynamic functional maturation process where a constitutive binding of inhibitory receptors to cognate HLA class I molecules is required for NK cells to maintain their full cytotoxic capacity. Previously, we described autoantibodies to CD94/NKG2A in patients with systemic lupus erythematosus (SLE). In this study we analyzed sera from 191 patients with SLE, 119 patients with primary Sjögren's syndrome (pSS), 48 patients with systemic sclerosis (SSc), and 100 healthy donors (HD) for autoantibodies to eight different KIRs. Anti-KIR autoantibodies were identified in sera from 23.0% of patients with SLE, 10.9% of patients with pSS, 12.5% of patients with SSc, and 3.0% of HD. IgG from anti-KIR-positive SLE patients reduced the degranulation and cytotoxicity of NK cells toward K562 tumor cells. The presence of anti-KIR-autoantibodies reacting with >3 KIRs was associated with an increased disease activity (p < 0.0001), elevated serum levels of IFN-α (p < 0.0001), nephritis (p = 0.001), and the presence of anti-Sm (p = 0.007), and anti-RNP (p = 0.003) autoantibodies in serum. Together these findings suggest that anti-KIR autoantibodies may contribute to the reduced function of NK cells in SLE patients, and that a defective NK cell function may be a risk factor for the development of lupus nephritis.

Clinical, Serological, and Histopathological Similarities Between Severe COVID-19 and Acute Exacerbation of Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD)

“…A recent preprint suggests significant extrafollicular B cell activation with an excessive production of antibody-secreting cells (ASCs) in critically ill SARS-CoV-2 patients ( 34 ). This mechanism is highly similar to the development and progression of SLE, and these ASC might represent a possible source of the autoantibodies we report here ( 35 , 36 ). We do not assume that these autoantibodies were already present in predisposed patients prior to infection, because only two patients in our cohort had any clinical history of rheumatic or autoimmune disease.…”

The Increased Ratio of Blood CD56bright NK to CD56dim NK Is a Distinguishing Feature of Primary Sjögren’s Syndrome

“…Increasing experimental evidence has shown a direct involvement of NK cells and CD56 NK cell subsets in some human immunopathologies such as psoriatic arthritis, SLE, multiple sclerosis, and Behcet's disease [19,[23][24][25]. However, as innate lymphoid cells, the role and clinical significance of CD56 NK cell subsets in pSS patients are poorly understood.…”

Natural Killer Cell Dysfunction and Its Role in COVID-19

“…Patients with SLE have a numerical deficit and a reduced cytotoxicity of NK cells. In addition, Sederberg et al, demonstrated that SLE patients may foster autoantibodies to both HLA class I-binding receptors (NKG2A, NKG2C), and multiple killer cell immunoglobulin-like receptors, which results in the dysregulation of self-nonself-recognition [ 22 , 25 ] ( Table 1 ).…”

“…Similarly to familial HLH, patients with systemic juvenile idiopathic arthritis (sJIA) harbor mutations in genes related to NK cell cytotoxicity [ 58 , 59 ]. MAS also occurs in adult onset Still’s disease [ 60 ] and systemic lupus erythematosus (SLE) [ 25 ], where in the latter autoantibodies targeting CD94 + , result in an increase in NK cell cytokine secretion [ 22 ].…”