Lymphoproliferative disease and acquired C1 inhibitor deficiency

Castelli, Roberto; Deliliers, Daniela Lambertenghi; Zingale, Lorenza C.; Pogliani, Enrico Maria; Cicardi, Marco

doi:10.3324/haematol.10769

Cited by 71 publications

(64 citation statements)

References 8 publications

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“…We studied L chain restriction implicated in anti-FH reactivity. With regard to the anti-C1 inhibitor leading to acquired deficiency (50,51), we showed that the anti-FH autoantibodies possessed the same L chain as monoclonal Ig, suggesting that MG may be responsible for anti-FH reactivity. Thus, the ratio of k/l anti-FH reactivity could be a reliable marker of the evolution of GP in the context of MG (52).…”

Section: Discussionmentioning

confidence: 94%

Anti–Factor H Autoantibodies in C3 Glomerulopathies and in Atypical Hemolytic Uremic Syndrome: One Target, Two Diseases

Blanc

Togarsimalemath

Chauvet

et al. 2015

The Journal of Immunology

105

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Autoantibodies targeting factor H (FH), which is a main alternative complement pathway regulatory protein, have been well characterized in atypical hemolytic uremic syndrome (aHUS) but have been less well described in association with alternative pathway–mediated glomerulopathies (GP). In this study, we studied 17 patients presenting with GP who were positive for anti-FH IgG. Clinical data were collected and biological characteristics were compared with those of patients presenting with anti-FH Ab-associated aHUS. In contrast to the aHUS patients, the GP patients had no circulating FH-containing immune complexes, and their anti-FH IgG had a weaker affinity for FH. Functional studies demonstrated that these Abs induced no perturbations in FH cell surface protection or the binding of FH to its ligand. However, anti-FH IgG samples isolated from three patients were able to affect the factor I cofactor activity of FH. Epitope mapping identified the N-terminal domain of FH as the major binding site for GP patient IgG. No homozygous deletions of the CFHR1 and CFHR3 genes, which are frequently associated with the anti-FH Ab in aHUS patients, were found in the GP patients. Finally, anti-FH Abs were frequently associated with the presence of C3 nephritic factor in child GP patients and with monoclonal gammopathy in adult GP patients, who frequently showed Ig Lchain restriction during reactivity against factor H. These data provide deeper insights into the pathophysiological differences between aHUS and GP, demonstrating heterogeneity of anti-FH IgG.

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Section: Discussionmentioning

confidence: 94%

Anti–Factor H Autoantibodies in C3 Glomerulopathies and in Atypical Hemolytic Uremic Syndrome: One Target, Two Diseases

Blanc

Togarsimalemath

Chauvet

et al. 2015

The Journal of Immunology

105

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“…In most cases of C1-INH-AAE, an underlying disorder, such as a lymphoproliferative disease (B-NHL) or autoimmune disease, can be found (64,65). However, as in other autoimmune disorders, AAE might also be a herald of future autoimmune disease or lymphoma, respectively.…”

Section: C1-inhibitor Regulates Bk Generationmentioning

confidence: 99%

Hereditary and acquired C1-inhibitor-dependent angioedema: from pathophysiology to treatment

Zeerleder

Levi

2016

Annals of Medicine

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Uncontrolled generation of bradykinin (BK) due to insufficient levels of protease inhibitors controlling contact phase (CP) activation, increased activity of CP proteins, and/or inadequate degradation of BK into inactive peptides increases vascular permeability via BK-receptor 2 (BKR2) and results in subcutaneous and submucosal edema formation. Hereditary and acquired angioedema due to C1-inhibitor deficiency (C1-INH-HAE and -AAE) are diseases characterized by serious and potentially fatal attacks of subcutaneous and submucosal edemas of upper airways, facial structures, abdomen, and extremities, due to inadequate control of BK generation. A decreased activity of C1-inhibitor is the hallmark of C1-INH-HAE (types 1 and 2) due to a mutation in the C1-inhibitor gene, whereas the deficiency in C1-inhibitor in C1-INH-AAE is the result of autoimmune phenomena. In HAE with normal C1-inhibitor, a significant percentage of patients have an increased activity of factor XIIa due to a FXII mutation (FXII-HAE). Treatment of C1-inhibitordependent angioedema focuses on restoring control of BK generation by inhibition of CP proteases by correcting the balance between CP inhibitors and BK breakdown or by inhibition of BK-mediated effects at the BKR2 on endothelial cells. This review will address the pathophysiology, clinical picture, diagnosis and available treatment in C1-inhibitor-dependent angioedema focusing on BK-release and its regulation. ä KEY MESSAGESInadequate control of bradykinin formation results in the formation of characteristic subcutaneous and submucosal edemas of the skin, upper airways, facial structures, abdomen and extremities as seen in hereditary and acquired C1-inhibitor-dependent angioedema. Diagnosis of hereditary and acquired C1-inhibitor-dependent angioedema may be troublesome as illustrated by the fact that there is a significant delay in diagnosis; a certain grade of suspicion is therefore crucial for quick diagnosis. Submucosal edema formation in hereditary and acquired C1-inhibitor-dependent angioedema is potentially life threatening and can occur at any age. To date effective therapies for acute and prophylactic treatment are available. ARTICLE HISTORY

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“…Its pathogenesis is related to the consumption of C1-INH by neoplastic lymphatic tissues and/or the formation of anti-C1 inhibitor neutralizing autoantibodies [9]. Interestingly, the first AE attack often predates by several years the onset of hematological disease [10].…”

Section: Acquired Aementioning

confidence: 99%

Hereditary and Acquired Angioedema: Heterogeneity of Pathogenesis and Clinical Phenotypes

Bova

Feo

Parente

et al. 2018

Int Arch Allergy Immunol

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Recurrent angioedema (AE) without wheals is increasingly recognized as a clinical entity and a frequent cause of admission to the emergency room. The Hereditary Angioedema Working Group (HAWK) classification allowed the scientific community to go beyond the semantic confusion that dominated this topic for decades. This classification distinguishes hereditary and acquired forms of AE, either related or unrelated to C1 inhibitor deficiency. Recently, additional mechanisms have been involved in the AE pathogenesis, including the uncontrolled activation of factor XII, generation of vasoactive mediators that induce dysregulation of endothelial functions, and bidirectional interactions between mast cell-derived mediators and the plasma contact system. Thus, recurrent AE can be determined by multiple and concurrent mechanisms that may generate distinct clinical phenotypes of the disease. Frequency, severity, and the location of attacks are quite different from patient to patient and, even in the same patient, they may change throughout the course of life. The severity of the clinical phenotype strongly influences the burden of the disease and patients’ quality of life. Despite major advances in our understanding of recurrent AE, many unsolved questions remain, leaving several unmet needs for patients and caregivers. This review is focused on a description of different AE phenotypes and the concurrent mechanisms leading to their pathogenesis. A better definition of cellular and molecular pathways responsible for the distinct AE phenotypes may help to improve diagnosis and may lead to a personalized approach to prophylaxis and treatment of the disease.

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Lymphoproliferative disease and acquired C1 inhibitor deficiency

Cited by 71 publications

References 8 publications

Anti–Factor H Autoantibodies in C3 Glomerulopathies and in Atypical Hemolytic Uremic Syndrome: One Target, Two Diseases

Anti–Factor H Autoantibodies in C3 Glomerulopathies and in Atypical Hemolytic Uremic Syndrome: One Target, Two Diseases

Hereditary and acquired C1-inhibitor-dependent angioedema: from pathophysiology to treatment

Hereditary and Acquired Angioedema: Heterogeneity of Pathogenesis and Clinical Phenotypes

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