CHAPLE disease (Complement Hyperactivation, Angiopathic Thrombosis, and Protein-Losing Enteropathy [PLE]) is a rare, life-threatening disorder caused by biallelic mutations in the CD55 gene, which encodes decay-accelerating factor, a key regulator of the complement system. The disease typically manifests in early childhood with hypoalbuminemic edema, gastrointestinal symptoms, recurrent infections, and failure to thrive, alongside an elevated thrombotic risk due to complement-mediated endothelial injury and coagulation activation. Given these pathogenetic mechanisms, complement-targeted therapies have emerged as a rational approach to disease management. Eculizumab, a monoclonal antibody against complement component C5, initially demonstrated clinical benefit when administered on a compassionate-use basis. Building upon this success, pozelimab, a next-generation subcutaneous anti-C5 monoclonal antibody, was evaluated in CHAPLE patients and subsequently received U.S. FDA approval for this indication. Pozelimab effectively inhibits terminal complement activation, leading to sustained remission of PLE, obviating the need for albumin replacement, reducing hospitalization rates, improving symptom control and nutritional status, and ultimately enhancing overall quality of life. This review highlights the evolving role of pozelimab in CHAPLE disease by discussing its mechanistic basis, emerging clinical evidence, and implications for patient-centered care. CHAPLE disease is a very rare and serious condition that starts in early childhood. It is caused by mutations in a gene called CD55, which normally helps control the body’s immune system, especially a part called the complement system. When this system is not controlled properly, it attacks the body’s own blood vessels, lymphatic vessels, and organs.Children with CHAPLE often have swelling from low protein levels, stomach problems (like pain, vomiting, and diarrhea), frequent infections, and poor growth. They are also at high risk of dangerous blood clots.The main problem in CHAPLE is damage to lymphatic vessels in the intestines and abnormal clotting caused by overactive immune responses. This leads to loss of protein from the intestines and other serious complications.Treatments that target the overactive complement system have shown promise. One such drug, eculizumab, helped patients with this condition. A newer medicine called pozelimab, administered by subcutaneous injection, has now been approved by the FDA. It works by blocking part of the immune system that causes the damage.Pozelimab has helped CHAPLE patients by stopping protein loss, improving growth and nutrition, and enhancing overall quality of life. This review explains how pozelimab works, what the latest research shows, and how it transforms CHAPLE care.

Viruses of the family Anelloviridae represent a predominant component of the human virome across various anatomical sites, yet their clinical significance remains poorly understood. This review summarizes current data on the dynamics and functional interactions of anelloviruses with the immune system in the context of human immune deficiency virus (HIV) infection. Existing studies indicate that an individual's complement of anelloviruses (their "anellome") serves as a highly sensitive indicator of immunocompetence. In the absence of antiretroviral therapy (ART), the viral load and taxonomic diversity of anelloviruses (genera Alphatorquevirus, Betatorquevirus, and Gammatorquevirus) demonstrate a rapid increase, correlating with HIV viral load, a decline in CD4+ T-lymphocyte count, and the CD4/CD8 ratio, reflecting weakened immune surveillance. Upon initiation of antiretroviral therapy (ART), a decrease in anellovirus viral load is observed; however, it likely does not revert to the pre-HIV infection baseline. At the same time, a high baseline level of Torque teno virus (TTV) is associated with incomplete immune recovery and the risk of ART non-response. Anelloviruses exhibit a dual role as both activators of the immune system (via APOBEC3, antibody production, and pro-inflammatory cytokines resulting from Toll-like receptor (TLR) activation) and disruptors of certain signaling pathways (through micro-RNAs and proteins encoded by ORF2). Thus, monitoring the anellome represents a promising non-invasive approach for assessing immune status, risk stratification, and personalizing therapy in patients with HIV infection. Future research should focus on the practical application of anellovirus viral load and diversity as markers of immune status and on clarifying the consequences of the aggregate interaction between HIV modulator proteins and anelloviruses during co-infection.

The complement system is a central component of innate immunity, mediating opsonization, chemotaxis, cytolysis, and shaping adaptive responses. Deficiencies in complement proteins, whether inherited or acquired, predispose to severe infections, particularly with encapsulated bacteria such as Neisseria meningitidis and Streptococcus pneumoniae. Although rare, inherited defects affect different pathways and may also present with autoimmune or renal diseases. Diagnosis relies on functional and quantitative assays, especially in patients with early-onset or recurrent infections. Complement inhibition, introduced with eculizumab and expanded to agents targeting C3, Factor B, or Factor D, has transformed the management of complement-mediated disorders but unmasked novel infectious risks, including meningococcal disease and invasive fungal infections. This review summarizes clinical and mechanistic aspects of complement deficiencies, infection risks associated with therapeutic blockade, and current diagnostic strategies. It emphasizes the importance of anticipatory care, vaccination, and prophylaxis as new complement-targeted drugs continue to emerge.

Complement factor I (CFI) deficiency is an ultrarare inborn disorder of complement regulation that manifests with protean infectious, vasculitic, and neuroinflammatory symptoms. We sought to functionally validate a previously unrecognized, disease-associated CFI variant (Y459S) and determine variant enrichment in the Old Order Amish population. Expression and function of the CFI Y459S variant was evaluated via immunoblot, complement factor 3b degradation, and crystal structure analysis. CFI variant frequencies in Old Order Amish populations were determined using genomic databases hosted by the Clinic for Special Children and the Anabaptist Variant Server. Patient samples were assessed for leukocyte frequencies, cytokine concentrations, and complement component concentrations in clinical laboratories. Neuroinflammatory assessments were made by review of brain and spine magnetic resonance imaging by a blinded neuroradiologist. Y459S conferred a loss of function to CFI. The CFI Y459S allele is enriched more than 4500-fold among the Old Order Amish (mean allelic frequency, 0.037), with 1 in every 730 live births in this population predicted to be homozygous. A single-center cohort of 11 Amish CFI Y459S homozygous patients identified 5 patients with critical neuroinflammatory diagnoses including acute disseminated encephalomyelitis, transverse myelitis, and aseptic meningoencephalitis. Features of CFI-deficient neuroinflammation included neutrophilic cerebral spinal fluid pleocytosis, constitutive complement activation, female predominance, diverse neuroimaging findings, and (in 1 case) a clinical response to eculizumab. CFI deficiency should be a key diagnostic consideration for patients with neuroinflammatory symptoms, neutrophilic cerebral spinal fluid pleocytosis, and complement consumption, especially if they belong to the Old Order Amish community.

The complement system is a central component of innate immunity, orchestrating pathogen clearance while regulating inflammation, tissue repair, and homeostasis. Its activation is tightly controlled by multiple inhibitors to prevent self-damage. However, complement dysregulation is implicated in numerous organ-specific diseases, including paroxysmal nocturnal hemoglobinuria (erythrocytes), atypical hemolytic uremic syndrome (kidneys), and age-related macular degeneration (eyes). Recent discoveries have revealed that complement hyperactivation also drives lymphatic dysfunction, most notably in CHAPLE (CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy) disease-a rare pediatric disorder caused by biallelic CD55 mutations. Impaired regulation of C3 and C5 convertases leads to unchecked complement and coagulation activation, resulting in membrane attack complex deposition, severe intestinal lymphangiectasia, and protein-losing enteropathy. Patients typically present with hypoalbuminemia, edema, gastrointestinal symptoms, growth retardation, and recurrent thromboembolic events, reflecting a severe thrombophilic phenotype. C5-blocking antibodies, including pozelimab and eculizumab, transformed CHAPLE management. In a phase 2/3 study, pozelimab led to normalization of serum albumin levels and notable reductions in hospitalizations and transfusion needs, leading to Food and Drug Administration approval. Emerging evidence suggests that complement-driven protein-losing enteropathy may also arise in other pathological contexts, expanding the clinical impact of complement dysregulation. As research progresses, novel diagnostic and therapeutic strategies are expected to emerge for a broader spectrum of complement-mediated lymphatic disorders.