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CHD Genetics Part II
Published in Mark C Houston, The Truth About Heart Disease, 2023
AGTR1(AT1R-AA) is related to autoantibodies and hypertension. An “autoantibody” is an abnormal antibody that is part of your immune system and which attacks your own organs (i.e., attacks “the self”). This autoantibody stimulates a receptor called angiotensin receptor I (AT1R) that causes hypertension and increases the risk for CHD and MI. This form of hypertension is best treated with an ARB.
Systemic Lupus Erythematosus
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
Vaneet K. Sandhu, Neha V. Chiruvolu, Daniel J. Wallace
Despite the 2019 EULAR/ACR criteria heavily emphasizing ANA as the entry criterion for the diagnosis of SLE, a positive ANA can be found in up to 30% of the general population and in other autoimmune conditions such as scleroderma, rheumatoid arthritis, Sjögren’s syndrome, and mixed connective tissue disease. ANA has been heavily criticized for its poor specificity,10 and there is emerging investigation into autoantigen arrays. Proteome microarray-based technology has been utilized for years to identify biomarkers in many diseases. Autoantigen arrays are used to screen and identify interactions between antigens and antibodies on a large scale.11 One of the benefits of this technology is that antibodies can be detected at a level of less than 1 ng/ml. Small samples, close to 1–2 microliters, can be obtained from serum, body fluids, or cell culture supernatant. Antibodies that bind to corresponding antigens on the array are detected using a fluorophore conjugate of second antibodies against different isotypes of autoantibodies (IgG, IgM, IGA, IgE). One of the marvels of autoantibody arrays is their capacity to detect hundreds of thousands of autoantibodies quantitatively and even prior to clinical onset of disease, thereby serving as an early diagnostic tool. Furthermore, quantification of antibodies may be helpful in monitoring disease activity and response to treatment. Data obtained from these arrays have demonstrated greater sensitivity in comparison to enzyme-linked immunosorbent assay (ELISA).12
Human Monoclonal Autoantibodies
Published in Thomas F. Kresina, Monoclonal Antibodies, Cytokines, and Arthritis, 2020
Susan Alpert Galel, Edward G. Engleman, Steven K. H. Foung
Most of the T cell-reactive antibodies we isolated show reactivity with other hematopoietic and some nonhematopoietic cell types. Therefore, it is possible that antilymphocyte autoantibodies may cause wide-ranging functional effects. Similarly, Shoenfeld et al. have found that the DNA-reactive monoclonal antibodies that they have isolated also show a remarkable degree of polyspecificity. That is, individual DNA-reactive monoclonal antibodies bind to a wide variety of targets, including native DNA, single-stranded DNA, synthetic polynucleotides, cardiolipin, lymphocytes, platelets, cytoskeletal proteins, and some mycobacterial antigens (6,43–46). However, there is significant variability from antibody to antibody in the precise pattern of cross-reactivity. The remarkable cross-reactivity of human monoclonal autoantibodies raises interesting questions regarding the original stimulus for such antibodies and raises the possibility that a single autoantibody could be involved in a wide range of clinical effects.
Plasma exchange as an adjunctive therapy in anti-neutrophil cytoplasm antibody-associated vasculitis
Published in Expert Review of Clinical Immunology, 2023
Kavita Gulati, Charles D Pusey
In nephrology, it was first utilized in 1975 to treat a patient with pulmonary-renal syndrome due to anti-glomerular basement (anti-GBM) disease [75]. Lockwood et al. went on to publish a case series, which showed great efficacy in early and rapid improvement in renal function and pulmonary hemorrhage [76]. All of the patients had reduction or complete suppression of autoantibody levels; however, it was clear that there was a requirement for ongoing immunosuppression to prevent resynthesis of the pathogenic autoantibodies [76]. This led Lockwood et al. to hypothesis that TPE would also be effective in treating patients presenting with RPGN and vasculitis in the absence of anti-GBM antibodies [77]. The success of this approach will be discussed later. At the time, it was postulated that there was an as yet unidentified immune complex driving the classical histological changes of crescentic glomerulonephritis. In retrospect, these patients probably had AAV with renal involvement.
Gut dysbiosis and the clinical spectrum in anti-Ro positive mothers of children with neonatal lupus
Published in Gut Microbes, 2022
Robert M. Clancy, Miranda C. Marion, Hannah C. Ainsworth, Miao Chang, Timothy D. Howard, Peter M. Izmirly, Mala Masson, Jill P. Buyon, Carl D. Langefeld
Autoantibodies can antecede overt clinical disease by years, as demonstrated by the fact that serological positivity for anti-SSA/Ro autoantibodies can be detected long before clinical symptoms of Systemic Lupus Erythematosus (SLE);1 however, autoantibody profiles alone cannot predict which patients will develop clinically significant disease versus those who will remain in a benign autoimmune state. In this respect, mothers whose children have neonatal lupus represent a unique population at risk for overt clinical autoimmunity. Despite the presence of high titer anti-SSA/Ro antibodies clearly pathogenic to the developing fetus, many women are asymptomatic and subsequently unaware of their autoantibody status, learning of their autoimmunity only because of disease in their offspring. Follow-up of these at-risk mothers in one U.S. registry revealed that women who were asymptomatic at the time of their child’s birth had 10-year probabilities of developing SLE and Sjögren’s Syndrome (SS) of 18.6% and 27.9%, respectively.2
Prospects for CAR T cell immunotherapy in autoimmune diseases: clues from Lupus
Published in Expert Opinion on Biological Therapy, 2022
Marko Radic, Indira Neeli, Tony Marion
Certain autoimmune diseases result from the effects of a single autoantibody specificity. Pemphigus is an autoimmune skin blistering disorder, in which autoantibodies play a central role. Most patients with pemphigus exhibit autoantibodies to desmoglein, a cadherin-like adhesion molecule that connects keratinocytes to each other and gives elasticity and cohesion to the epidermis [71]. Ellebrecht et al. [72] constructed CARs with extracellular domains derived from desmoglein to serve as ‘bait’ for anti-desmoglein B cells (Figure 3B). Upon binding to anti-desmoglein B cells, the redesigned chimeric autoantibody receptor (CAAR) triggers the specific killing of the autoreactive B cells. The success of this approach in animals provided preclinical data used in an application to the FDA for the initiation of clinical trials [73]. A similar approach has been developed for myasthenia gravis (MG), a progressive and debilitating disease with autoimmune disruption of acetylcholine receptor function at the neuromuscular junctions. A subset of patients with MG make autoantibodies to muscle signaling kinase (MuSK) and CAAR T cells using a portion of MuSK as the extracellular bait for autoreactive B cells are in early development (Oh S, 2020). Yet to be tested in the context of autoimmunity, a CAR T cell incorporating domains from a scavenging protein (Figure 3C) could offer an alternative approach to deplete excessive circulating IC, as shown by engineering in a phagocytic cell population [74].