C/EBPepsilon-Associated Autoinflammation and Immune Impairment of Neutrophils

CAIN is an autosomal dominant autoinflammatory disease caused by mutations in the CEBPE gene, which encodes the transcription factor C/EBPε that regulates the inflammasome. CAIN is characterized by a combination of:

• Autoinflammation
• immunodeficiency and
• neutrophil dysfunction

characterized by

The CCAAT enhancer-binding protein epsilon (C/EBPε) encoded by the CEBPE gene is a transcription factor involved in late differentiation of the myeloid lineage and cell function. The homozygous Arg219His mutation in the transcription factor C/EBPε is causative for an autoinflammatory disease with impaired neutrophil function. Mutated C/EBPε acts as a regulator of both the inflammasome and the interferome. The Arg219His mutation causes a monogenic non-canonical inflammasomopathy/immunodeficiency. The underlying pathomechanism, which includes highly dysregulated transcription, is probably not unique to C/EBPε.

Onset during adolescence; healing usually occurs after the menopause.

The clinical picture consists of periodic attacks of abdominal pain and high fever for 4-5 days every 2-4 weeks. Other manifestations during the attacks are oral ulcers, cutaneous abscesses, pyoderma gangrenosum, intra-abdominal granulomas and upper respiratory tract infections. Mild hemorrhagic diathesis with frequent nosebleeds and hematomas after needle sticks and surgical procedures have been described. ESR elevations are frequent.

Dermatologic manifestations: Crater-like ulcers of the buccal mucosa are the most common mucocutaneous features. Furthermore, recurrent abscessing inflammations of the tongue and buttocks as well as purulent paronychia, pyoderma gangrenosum and delayed wound healing are found.

In CAIN patients, the blockade of IL-1β and anti-IL-18 are potential therapeutic approaches that have not yet been tested (Göös H et al. 2019).

In addition to the autoinflammatory disease described here, which is associated with C/EBPε, an autosomal recessive neutrophil-specific granule deficiency is known to lead to severe impairment of neutrophil function and early mortality (Goos H et al. 2019).

2 Pakistani girls born to consanguineous parents suffered from severe AIDs beginning in the first weeks of life. Both had periodic febrile episodes of 3-7 days duration, every 6-12 weeks, with severe acute phase reactions: C-reactive protein, >270 mg/liter (reference range < 20); serum amyloid A, >200 mg/liter (RR < 10); leukocytosis, 32 × 109/liter (predominantly neutrophil granulocytes); hyperferritinemia, 82-2.679 µg/ml (RR 11-76); and thrombocytopenia, 24-90 × 109/liter; and normalization of these parameters between febrile episodes. Both had severe recurrent oral inflammation, leading to scarring and acquired microstomy in patient IV-2, and recurrent perianal ulceration. Genetic screening for common AIDs (TNFRSF1A, MVK, NLRP3 and MEFV) was negative. Frequent infections were also observed before immunosuppression. Patient IV-1 developed Pneumocystis jiroveci pneumonia at the age of 5 months and septic arthritis of the knee caused by Staphylococcus aureus at the age of 2 years. Patient IV-2 developed necrotizing erysipelas due to streptococcal pneumonia at the age of 13 years. Both developed severe inflammatory reactions to (presumed) viral infections with moderate thrombocytopenia. The mean platelet volume (MPV) was elevated in patient IV-2, while it was in the normal range in IV-4.

The bone marrow aspirate of patient IV-4 showed ultrastructural abnormalities of the megakaryocytes by electron microscopy. A detailed immunologic examination of both children ruled out autoimmunity, common primary immunodeficiency syndromes and primary hemophagocytic lymphohistiocytosis. In patient IV-4, T-cell stimulation with phytohemagglutinin (PHA) was normal, but T-cell activation in response to stimulation with anti-CD3 was decreased, suggesting a defect in adaptive immunity. Patient IV-2 had normal T-cell activation to PHA, but T-cell activation in response to anti-CD3 was not documented. Neutrophil respiratory activity and phagocytosis of opsonized Escherichia coli (in IV-4) were normal.

Both children responded partially to corticosteroids and colchicine, but poor growth and inflammatory episodes persisted. Patient IV-2 responded to several anti-inflammatory and immunosuppressive agents. However, there was some transient steroid-sparing effect in response to anakinra (2-4 mg/kg s.c. daily). Ultimately, however, this did not control the episodes of autoinflammation and the patient died at the age of 14 years from sterile systemic inflammation and multiorgan failure. Patient IV-4 underwent successful allogeneic hematopoietic stem cell transplantation (HSCT) at the age of 8 years and is still healthy 3 years later, without any medication (see Göös H et al. 2019).

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