Lymphadenopathy at the crossroad between immunodeficiency and autoinflammation: An intriguing challenge

Abstract

Lymphadenopathies can be part of the clinical spectrum of several primary immunodeficiencies, including diseases with immune dysregulation and autoinflammatory disorders, as the clinical expression of benign polyclonal lymphoproliferation, granulomatous disease or lymphoid malignancy. Lymphadenopathy poses a significant diagnostic dilemma when it represents the first sign of a disorder of the immune system, leading to a consequently delayed diagnosis. Additionally, the finding of lymphadenopathy in a patient with diagnosed immunodeficiency raises the question of the differential diagnosis between benign lymphoproliferation and malignancies. Lymphadenopathies are evidenced in 15-20% of the patients with common variable immunodeficiency, while in other antibody deficiencies the prevalence is lower. They are also evidenced in different combined immunodeficiency disorders, including Omenn syndrome, which presents in the first months of life. Interestingly, in the activated phosphoinositide 3-kinase delta syndrome, autoimmune lymphoproliferative syndrome, Epstein-Barr virus (EBV)-related lymphoproliferative disorders and regulatory T cell disorders, lymphadenopathy is one of the leading signs of the entire clinical picture. Among autoinflammatory diseases, the highest prevalence of lymphadenopathies is observed in patients with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) and hyper-immunoglobulin (Ig)D syndrome. The mechanisms underlying lymphoproliferation in the different disorders of the immune system are multiple and not completely elucidated. The advances in genetic techniques provide the opportunity of identifying new monogenic disorders, allowing genotype-phenotype correlations to be made and to provide adequate follow-up and treatment in the single diseases. In this work, we provide an overview of the most relevant immune disorders associated with lymphadenopathy, focusing on their diagnostic and prognostic implications.

Keywords: CTLA-4; LRBA; activated phosphoinositide 3-kinase δ syndrome; autoimmune lymphoproliferative syndrome; common variable immunodeficiency.

FIGURE 1

Immunodeficiency, immune dysregulation and autoinflammatory disorders associated with lymphadenopathy. The figure shows the classification of primary immunodeficiency disorders associated with lymphadenopathy, including immune dysregulation and autoinflammatory disorders. In particular, the significant overlap between T and B cell immunodeficiency and immune dysregulation disorders is highlighted

FIGURE 2

Frequency of lymphadenopathy in immunodeficiency, immune dysregulation and autoinflammatory disorders. *Fewer than 10 described patients. **Highly variable clinical phenotype

FIGURE 3

Summary of the molecular mechanisms leading to immune dysregulation syndromes. (a) The molecular mechanisms associated with the development of immune dysregulation in disorders with ineffective apoptosis. When the first apoptosis signal (FAS) binds FAS ligand (FASL), the apoptotic pathway is initiated, as FAS‐associated protein with death domain (FADD) promotes the activation of pro‐caspase 8 and pro‐caspase 10, responsible for the initiation of apoptosis. In autoimmune lymphoproliferative syndrome‐FAS (ALPS‐FAS), ALPSFASL) and ALPS‐caspase 10 (CASP10) the molecular defect is responsible for an impairment of the first molecular steps of the apoptotic cascade. Protein kinase C δ (PKC‐δ) promotes the apoptosis through a caspase‐3 dependent mechanism, and acts by down‐regulating the B cell receptor (BCR) and T cell receptor (TCR) signaling, thus reducing the lymphocyte proliferation. Therefore, in PKC‐δ deficiency (PKCD) the apoptotic defect is accompanied by enhanced lymphocyte proliferation. (b) Mechanisms responsible for immune dysregulation and lymphadenopathy in diseases affecting regulatory T cells (T_regs) functioning. Forkhead box protein 3 (FoxP3), which is deficient in immune dysregulation, polyendocrinopathy, enteropathy, X‐linked (IPEX), is central for T_regs proliferation and activity. CD25 is important in activating interleukin (IL)‐2‐dependent signaling, and therefore in promoting the transcription of FoxP3, which is impaired in CD25 deficiency. Signal transducer and activator of transcription (STAT)‐5b is an activator of FoxP3, which is inhibited by STAT‐3. In STAT‐3 gain‐of‐function (GOF), the enhanced inhibition of STAT‐5 finally leads to reduced FoxP3 activity and T_regs proliferation. Also, the BTB domain and CNC homolog 2 (BACH‐2) has a role in promoting T_reg proliferation, which is altered in patients with BACH2‐related immunodeficiency and autoimmunity (BRIDA). Cytotoxic T lymphocyte antigen 4 (CTLA‐4), through interaction with the co‐stimulatory molecules CD80/CD86 on the antigen‐presenting cells (APC) surface, reducing their availability for the interaction with CD28 expressed by T cells. CTLA‐4 deficiency results in ineffective inhibition of co‐stimulatory signaling, leading to enhanced activation of T cells. Finally, lipopolysaccharide‐responsive and beige‐like anchor (LRBA) inhibits the lysosomal degradation of CTLA‐4, and in LRBA deficiency with autoantibodies, T_reg cell defects, autoimmune infiltration and enteropathy (LATAI) a secondary CTLA‐4 deficiency is observed

FIGURE 4

Diagnostic approach to lymphadenopathies in patients with immune disorders. The figure shows an approach to the diagnosis of immune diseases (immunodeficiencies, immune dysregulation and autoinflammatory disorders) associated with lymphoproliferation. The approach is based on the identification of specific clinical signs, including features of autoimmunity (arthritis, cytopenia, endocrinopathy), the finding of eczema, specific infectious patterns, periodic disease course and respiratory involvement, in the form of granulomatous lymphocytic interstitial lung disease (GLILD)