IL-12 Receptor Deficiency

Etiology and Pathophysiology

Epidemiology

• Very rare disorder
• Exact prevalence unknown

Etiology

• Autosomal recessive inheritance pattern
• Caused by mutations in the genes that encode for the IL-12 receptor (IL-12Rβ, IL-12Rβ1, and IL-12Rβ2)
• IL-12 receptor deficiency is considered part of or a subtype of the condition Mendelian susceptibility to mycobacterial disease (MSMD), which is characterized by immune dysfunction of the following:
  • Interferon-gamma receptor 1 (IFN-gammaR1) and receptor 2 (IFN-gammaR2) 
  • Interleukin-12 (IL-12) and IL-12 receptor (most common)
  • Interferon-stimulated gene 15 (ISG15) protein
  • Signal transducer and activator of transcription 1 (STAT1)
  • Interferon regulatory factor 8 (IRF8)

Pathophysiology

• IL-12:
  • Encoded by 2 separate genes, IL-12A (p35) and IL-12B (p40)
  • Produced by activated antigen-presenting cells (e.g., dendritic cells, macrophages)
  • Promotes transition of naive T-helper cells into Th1 cells, which release IFN-γ to activate macrophages, leading to cytotoxic protection
  • Essential for protective immunity against intracellular bacteria such as mycobacteria and Salmonella
• Mutations in IL-12 receptors result in an impaired Th1 response and decreased IFN-γ secretion, resulting in disseminated infections.

Clinical Presentation

• Recurrent disseminated infections in early childhood, with first infection usually occurring by age 3
  • Tuberculosis (TB) and non-TB mycobacterial infections
  • Salmonellosis
  • Disseminated infection after bacille Calmette-Guerin (BCG) vaccine 
  • Mucocutaneous candidiasis
• Infections can involve bone marrow (osteomyelitis), lungs (pneumonia), skin (cellulitis, abscesses), and lymph nodes (lymphadenitis), among other areas
• Often presents as sepsis (e.g., fever, rigors, hypotension) and disseminated intravascular coagulation (DIC)
• Infections are often disseminated but can also be limited to specific organs, especially the lungs or liver (pneumonitis or hepatitis, respectively).

Diagnosis and Management

Diagnosis

• Clinical suspicion arises after recurrent and disseminated infections with intracellular pathogens (e.g., Salmonella, Mycobacterium) in early childhood.
• Laboratory studies will reveal low levels of decreased IFN-γ.

Management

• There is no cure for IL-12 receptor deficiency, but the resulting infections can be treated with antibiotics and antifungals.
• IFN-γ administration aids in macrophage activation.
• Prognosis: mortality rate of 30% due to disseminated infections

Differential Diagnosis

The following conditions are differential diagnoses for IL-12 receptor deficiency:

• Autosomal dominant hyper-IgE syndrome: also known as Job’s syndrome, a rare form of primary immunodeficiency disorder that affects various organ systems in addition to the immune system. Caused by mutations in the STAT3 gene, it results in abnormal neutrophil chemotaxis. Patients present with recurrent pneumonia, skin infections, rashes, blisters, and abscesses.
• Cystic fibrosis: an autosomal recessive disorder caused by mutations in the CFTR gene. The mutations lead to dysfunction of chloride channels, which results in hyper viscous mucus and the accumulation of secretions. Common presentations include chronic respiratory infections, failure to thrive, and pancreatic insufficiency. 
• Chronic granulomatous disease: a chronic disorder that is characterized by granuloma formation. This disorder is a consequence of dysfunctional phagocytic cells that are unable to produce bactericidal superoxide due to a defect in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in these cells. Presentation includes recurrent skin infections, pneumonia, and gastroenteritis.
• Severe combined immunodeficiency (SCID): the most severe form of primary immunodeficiency. The condition is a genetic disorder that involves defective antibody response due to either direct involvement with B lymphocytes or through improper B-lymphocyte activation due to non-functional T-helper cells. Presents as severe and recurrent opportunistic infections and is diagnosed through quantitative polymerase chain reaction (PCR) and flow cytometry.