Mechanisms of Autoantibody-Induced Pathology

Abstract

Autoantibodies are frequently observed in healthy individuals. In a minority of these individuals, they lead to manifestation of autoimmune diseases, such as rheumatoid arthritis or Graves' disease. Overall, more than 2.5% of the population is affected by autoantibody-driven autoimmune disease. Pathways leading to autoantibody-induced pathology greatly differ among different diseases, and autoantibodies directed against the same antigen, depending on the targeted epitope, can have diverse effects. To foster knowledge in autoantibody-induced pathology and to encourage development of urgently needed novel therapeutic strategies, we here categorized autoantibodies according to their effects. According to our algorithm, autoantibodies can be classified into the following categories: (1) mimic receptor stimulation, (2) blocking of neural transmission, (3) induction of altered signaling, triggering uncontrolled (4) microthrombosis, (5) cell lysis, (6) neutrophil activation, and (7) induction of inflammation. These mechanisms in relation to disease, as well as principles of autoantibody generation and detection, are reviewed herein.

Keywords: B cells; autoantibodies; autoimmunity; diagnosis; mouse models; pathogenesis; treatment.

Figures

Figure 1

Multiple pathways lead to autoantibody-induced pathology. Depending on the targeted autoantigen, and sometimes even depending on the targeted epitope within a single autoantigen, autoantibodies induce pathology through specific and distinct mechanisms. Some are highlighted in this cartoon (from upper left to lower right): antibodies against the thyrotropin receptor (TSHR) mimic hormone stimulation of the TSHR receptor leading to hyperthyroidism, blockade of neural transmission by autoantibody binding to the corresponding receptors may lead to severe neurological diseases such as anti-N-methyl-d-aspartate encephalitis, autoantibody-mediated blockade of enzymes of the primary hemostasis may trigger uncontrolled microthrombosis, in pemphigus, autoantibodies induce an altered signaling in keratinocytes, which either reflects or leads to, a loss of cell–cell adhesion, resulting in severe skin blistering, autoantibodies to antigens expressed by neutrophils can lead to their uncontrolled activation, resulting in severe tissue injury, in autoimmune idiopathic thrombocytopenia autoantibodies trigger thrombocytopenia and severe bleeding, Fcγ-mediated functions may trigger tissue inflammation in many autoimmune diseases, e.g., rheumatoid arthritis and pemphigoid disease.

Figure 2

T/B cell cross talk in generating the autoimmune response. Autoantibodies can either promote or inhibit inflammation, depending on their immunoglobulin-isotype and glycosylation/sialylation patterns of their Fc-regions. Signals from both antigen-presenting B cells to T cells and from T cells to B cells, together, determine the inflammatory/anti-inflammatory property of the antibody response.

Figure 3

Mechanisms in thyroid autoimmunity. (A) Location of the thyroid gland in relation to the larynx and trachea and schematic representations of a thyroid follicle in a healthy individual (cuboidal cells) with the location of the thyroid-stimulating hormone receptor (TSHR), thyroglobulin, and thyroid peroxidase (TPO); a stimulated follicle in a patient with thyroid-stimulating autoantibodies (TSAb) (Graves disease; columnar epithelial cells); and a follicle in a patient with TSH blocking antibodies (TBAb) (atrophic goiter; very thin epithelial cells). Thyroid hormones (T4, T3) are elevated and TSH levels are very low in Graves’ disease; conversely, T4 and T3 are low and TSH is elevated TSH levels in atrophic goiter. (B) Representation of the TSH holoreceptor including its transmembrane domain (left) and the TSHR A-subunit (right) shed after cleavage.

Figure 4

Overview of mechanisms by which anti-AT1R and anti-ETAR induce systemic sclerosis (SSc) pathogenesis. (A)In vitro and (B)in vivo effects of autoantibodies targeting ETAR and AT1R in SSc are shown. Abbreviations: AT1R, angiotensin II type 1 receptor; ETAR, endothelin-1 type A receptor; PKC-α, protein kinase C-α; ERK1/2, extracellular signal-regulated kinase 1/2; NF-κB, nuclear factor-κB; AP-1, activator protein 1; TGF-β, transforming growth factor β; CCL18, chemokine (C-C motif) ligand 18; VCAM-1, vascular cell adhesion molecule-1.

Figure 5

Schematic illustration of the two major pathogenic mechanisms of autoantibodies to acetylcholine receptor (AChR). (1) Autoantibody binding to the AChR on the surface of postsynaptic muscle membrane activates the complement cascade, resulting in the formation of membrane attack complex (MAC) and localized destruction of the postsynaptic membrane. The immune assault releases shedding of membrane fragments containing AChRs into the synaptic cleft, and leads to a simplified, altered morphology of the postsynaptic membrane. (2) Autoantibodies cross-link AChR molecules on the postsynaptic muscle membrane, causing endocytosis of the cross-linked AChR molecules and their degradation (antigenic modulation). This leads to a reduced number of AChR molecules on the postsynaptic membrane.

Figure 6

Schematic illustration of mechanism of antibody-mediated feedback suppression. Cross-linking of the B-cell receptor and the inhibitory IgG receptor (FcγRIIB) on the B cell surface by antigen–antibody complex may result in apoptosis of antigen-specific B cells, inhibition of B cell activation by helper T cells, and inhibition of B cell proliferation. Cross-linking FcγRIIB on the surface of plasma cells by immune complexes induces apoptosis of plasma cells.

Figure 7

Pathophysiology of anti-N-methyl-d-aspartate-receptor (NMDAR) encephalitis. Details are explained in the text, where the numbering corresponds to the labeling used here. In brief, ectopic expression of NMDA receptors in ovarian teratomas together with co-stimulatory signals (A) or unknown triggers (B) lead to systemic immune response and formation of antigen-specific circulating B-, T-, and plasma cells producing NMDAR antibodies (1–4). The latter do not reach neurons in sufficient concentratiosn to exert effects due to the blood–brain barrier (dashed line). An unknown secondary trigger (e.g., systemic infections, 5) eventually mediates transition of B-, T-, and plasma cells into the brain. The resulting antibody production effectively increases intrathecal NMDAR antibody concentration above a threshold overwhelming neuronal compensation mechanisms and leading to net loss of surface NMDAR resulting in neurological symptoms. Adapted from Moscato et al. (216).

Figure 8

Autoantibody-induced loss of cell–cell adhesion in pemphigus. For explanation, please refer to the text.

Figure 9

Structure of ADAMTS13 and the frequency of autoantibodies targeting specific domains and graphical representation of the pathophysiology of acquired thrombotic thrombocytopenic purpura (TTP). (A) ADAMTS13 consists of a metalloprotease (M; orange) and disintegrin-like (D; blue) domain, a thrombospondin type-1 repeat (T1; green), a cysteine-rich (C; purple) and spacer (S; pink) domain, seven additional thrombospondin type-1 repeats (T2–T8; green), and two CUB domains (CUB1-2; red). Epitope mapping of anti-ADAMTS13 autoantibodies revealed that most patients (90–100%) have autoantibodies against the cysteine-spacer domain (indicated with the largest antibody). The size of the other antibodies in this figure demonstrates the relative frequency of these autoantibodies in the plasma of acquired TTP patients. (B) In normal conditions, UL-VWF released from activated endothelial cells is directly proteolysed by ADAMTS13, preventing spontaneous platelet binding. In the pathophysiology of acquired TTP, autoantibodies inhibit ADAMTS13 activity. UL-VWF multimers accumulate in the circulation and spontaneously bind platelets. This process results in the formation of VWF-rich microthrombi blocking the circulation in microcapillaries and arterioles.

Figure 10

Pathogenesis of inflammation and blistering in the pemphigoid disease epidermolysis bullosa acquisita. Details are explained in the text, where the numbering corresponds to the labeling used here.

Figure 11

Potential pathomechanisms in autoantibody-induced carditis and therapeutic options. Release of self-antigens through cardiomyocte damage caused by exogenous or endogenous factors can induce an autoimmune response against myocardial tissue in genetic predisposed patients leading to secondary myocardial damage. Therapeutic options could be immunoadsorption, treatment with intravenous immunoglobulin (IVIG) and/or immunosuppressive medication.

Figure 12

Autoantibody-dependent pathology in inflammatory arthritis. Shown are the autoantibody-driven processes that contribute to inflammation and bone destruction in inflammatory arthritis. Upon autoantibody deposition in the joints (1) tissue resident macrophages or mast cells become activated via Fcγ-receptors and release pro-inflammatory cytokines (including activated complement components) and chemokines (2). This leads to the recruitment of neutrophils and classical monocytes from the blood, leading to full-blown joint inflammation (3). The cytokine milieu favors the fusion of classical monocytes and their differentiation into immature osteoclasts (4). Immune complexes present in the joint bind to immature osteoclasts via FcgRs, which enhances their maturation into mature bone resorbing osteoclasts (5). Refer to the text, for a more detailed description.

Figure 13

Neuromyelitis optica spectrum disorder pathogenesis mechanisms. Scheme shows astrocyte aquaporin-4 (AQP4) as the target of AQP4-IgG autoantibodies. Antibody binding initiates complement and cell-mediated cytotoxicity and an inflammatory response, resulting in oligodendrocyte injury and demyelination. Abbreviations: CDC, complement-dependent cytotoxicity; ADCC, antibody-dependent cellular cytotoxicity.

Figure 14

Detection of autoantibodies. Details are explained in the text. Abbreviations: ELISA, enzyme-linked immunosorbent assay; FIPA, fluorescence immunoprecipitation assay; IFA, indirect immunfluorescence assay; RIA, radioimmunoassay.