Acquired C1-inhibitor deficiency and lymphoproliferative disorders: A tight relationship
Introduction
The clinical characteristics of acquired C1-inhibitor deficiency or acquired angioedema (AAE) are similar to those of hereditary C1-inhibitor deficiency known as hereditary angioedema (HAE), except for the later onset of symptoms, the absence of a family history, and the potential association with lymphoproliferative diseases and/or anti-C1-inhibitor auto-antibodies [1], [2]. Scattered reports describe acquired C1-inhibitor deficiency associated with nonhematologic neoplasm, infections or autoimmune diseases, whereas 14% of patients with acquired C1-inhibitor deficiency have no other disease [2]. The symptoms include recurrent, self-limiting local swelling located in the subcutaneous tissues (which may be disfiguring), the upper airways (which may cause possibly fatal laryngeal edema), and the gastrointestinal tract (which induces bowel obstruction and severe abdominal pain) [2], [3], [4].
A deficiency in C1-inhibitor leads to the activation of the classic complement pathway and consumption of C1, C2 and C4 components; furthermore, the contact system becomes unstable and prone to generate kallikrein, which cleaves high-molecular-weight kininogen (HK) and thus releases bradykinin, the mediator of the increased vascular permeability [5], [6], [7], [8], [9], [10]. The release of bradykinin is facilitated by the plasmin [11] generated during edema attacks in patients with C1-inhibitor deficiency [10], [12]. The mechanisms responsible for the consumption of C1-inhibitor and the massive activation of the classic complement pathway have been extensively investigated [1], [13], [14], [15], and the initial experiments indicated that C1-inhibitor and/or the classic complement pathway are consumed by neoplastic lymphatic tissues; moreover, C1-inhibitor can be cleaved/inactivated by its auto-antibody.
The majority of patients carry an underlying B cell disorder which is thought to cause C1-inhibitor consumption. These disorders range from the production of anti-C1-inhibitor auto-antibodies to monoclonal gammopathy of uncertain significance (MGUS) and non-Hodgkin lymphoma (NHL) [16], [17]. The relationship between pathological B cell clones and C1-inhibitor deficiency is easily identified when the clone produces auto-antibodies that cleave/inactivate C1-inhibitor, but it is not immediately obvious in the case of MGUS or NHL. Under these conditions, the presence of a cause-effect relationship between the pathological clone and C1-inhibitor consumption is supported by: (1) the prevalence of MGUS and NHL extraordinarily higher in AAE patients compared to the general population [16], [18]; (2) isolated reports showing various degrees of reversal of the biochemical and/or clinical abnormalities of AAE upon the therapeutically induced remission of NHL [18], [19], [20]; and (3) some experimental evidence suggesting that lymphatic tissues from AAE patients absorb or consume C1-inhibitor [1], [13], [14], [15].
We here review the pathophysiological mechanisms of AAE by concentrating on the relationship between it and the associated B cell disorders, and underline the potential reversal of complement abnormalities after treating the lymphoproliferative disease.
Section snippets
Historical background and pathophysiology of acquired c1-inhibitor deficiency
An acquired C1-inhibitor deficiency resulting in angioedema symptoms was first described in 1972 by Caldwell et al. [1], who observed it in a patient with a lymphoproliferative disorder. In 1986, Jackson et al. [13] discovered an autoreactive immunoglobulin G against C1-inhibitor in a patient with angioedema and acquired C1-inhibitor deficiency. These and other findings indicated that the pathogenetic mechanism underlying acquired C1-inhibitor deficiency may be related to autoimmunity [21], [22]
Presentation
The typical symptom of both hereditary and acquired C1-inhibitor deficiency is angioedema, a recurrent, self-limiting, non-pitting, non-pruritic edema that completely resolves in 1–5 days [2], [37], [38], [39]. Angioedema affects the subcutaneous tissue, the gastrointestinal mucosa, and the mucosa of upper respiratory tract. Angioedema of the skin causes deformities that may involve the face, genitals, buttocks, and extremities. Urticaria is usually absent, although transient and mild
Link between acquired angioedema and lymphoproliferative disease
AAE is frequently associated with lymphoproliferative disorders of B cell lineage ranging from MGUS to NHL. Three studies by our group have previously demonstrated that patients with acquired C1-inhibitor deficiency are at higher risk of developing NHL than the general population [16], [17], [18]. A lymphoproliferative disease may be present at the onset of AAE symptoms, or may develop thereafter (in our experience, between three months and seven years after) [18]. The most frequent
Conclusions
Although the etiology of acquired C1-inhibitor deficiency is still partially unclear, the majority of patients present an underlying B cell disorder, which ranges from the simple production of C1-inhibitor auto-antibodies to MGUS and NHL. The most frequent histotypes are nodal and splenic marginal zone lymphomas and lymphoplasmocytic lymphomas/Waldeström disease. The association with such histotypes is similar to that of other autoimmune diseases and, as they develop during the post-antigen
Conflicts of interest
The authors have no conflicting interests to disclose.
Reviewer
Teresa Caballero, MD, PhD, Senior consultant, Hospital Universitario La Paz, Allergy Department, Paseo de la Castellana 261, ES-28046 Madrid, Spain.
Massimo Cugno MD, is an associate professor of Internal Medicine at the University of Milan. He is the chief of the Center for the study of complement at the Maggiore Hospital in Milan. He graduated “cum laude” from the University of Milan in 1982. He completed his post-graduated speciality in Hematology and Internal Medicine at the University of Milan. He is involved in research on prognostic, therapeutic and biological aspects of hematological disorders. The scientific work was conducted
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Massimo Cugno MD, is an associate professor of Internal Medicine at the University of Milan. He is the chief of the Center for the study of complement at the Maggiore Hospital in Milan. He graduated “cum laude” from the University of Milan in 1982. He completed his post-graduated speciality in Hematology and Internal Medicine at the University of Milan. He is involved in research on prognostic, therapeutic and biological aspects of hematological disorders. The scientific work was conducted mainly in the field of proteasic systems, coagulation, fibrinolysis and complement. He has published around 150 original papers (130 in journals included in PubMed, some of excellence as New Engl J Med, Lancet, J Clin Invest, Am J Hum Genet, Circulation, and Blood).