Interferonopathies Complete Overview

What is Interferons

Interferons are a variety of polypeptides produced by virally-infected & immune cells, which tend to limit viral replication & viral propagation.

Types

• IFN-α – Produced by Viral infected cells (WBCs)
• IFN-β – Produced by Fibroblasts infected by viruses
• IFN-γ – NK cells, lymphocytes
• Others – IFN-ε, IFN-δ, IFN-ω

Type 1 IFN Pathway

• When there will be infections, Type 1 IFN will be produced
• Type 1 IFNs (e.g., IFN-α, β, κ) bind to the IFN Receptor (IFNR-α/β).
• This activates the JAK-STAT Pathway. This will lead to activation of IFN-Stimulated Genes (ISGs) → Stops replication of infected cells and decreases protein translation.
• Type 1 IFN pathway has both Autocrine & Paracrine signalling.

What are Interferonopathies?

Also called Type I Interferonopathies. Refer to a group of inherited auto-inflammatory disorders that are characterized by dysregulation of the Type I IFN pathway. Recent research indicates some autoimmune disorders, such as monogenic forms of SLE, may have disturbances in the Type I IFN pathway.

Mechanisms Producing IFNopathies

Any of the following:

• Loss of function of genes controlling DNA/RNA degradation
• Constitutive activation of intracytosolic nucleic acid sensors
• Gain of function in + IFN signal regulators
• Loss of function in – IFN signal regulators
• Proteasomal dysfunction causing unfolded protein - IFN Pathway activation inappropriately

Common Clinical Phenotype

• Recurrent Fevers
• Early-onset vasculopathy with chilblains
• Livedo reticularis
• Panniculitis
• Lipodystrophy
• ILD with fibrosis
• Encephalopathy
• Some patients may develop Pseudo-TORCH manifestations

List of Important IFNopathies  

• Aicardi-Goutieres Syndrome (AGS)
• Spondyloenchondrodysplasia (SPENCD)
• SAVI
• CANDLE Syndrome
• ISG15/USP18 Deficiency
• Singleton-Merten Syndrome
• X-linked Reticulate Pigmentary Disorder
• DNase-II Deficiency

Individual Autoinflammatory IFNopathies

Aicardi-Goutieres Syndrome (AGS)

• A spectrum of disorders, with 7 subtypes (AGS 1-7)
• Genetic Basis: Characterised by abnormalities in degradation/detection of DNA or DNA-RNA hybrid
• Subtypes:
  • AGS-1 (Gene mutation: TREX-1 mutation)
  • AGS-2 (Gene mutation: RNASEH2B mutation)
  • AGS-3 (Gene mutation: RNASEH2C mutation)
  • AGS-4 (Gene mutation: RNASEH2A mutation)
  • AGS-5 (Gene mutation: SAMHD1 mutation)
  • AGS-6 (Gene mutation: ADAR mutation)
  • AGS-7 (Gene mutation: IFIH-1 mutation)
  • Mostly AR (Autosomal Recessive), AGS-7 is the only AD (Autosomal Dominant)

Classical AGS - Clinical Presentation

• Onset: Infancy
• Clinical Features:

1. Progressive Encephalopathy:
   • Irritability, Recurrent Fever, Limb Hypertonia with Truncal Hypotonia
   • Neuro regression, Dystonia
   • Seizures, Abnormal eye movements, Exaggerated Startle Response
   • Progressive Microcephaly
2. Cutaneous (30%): Chilblains (digits, pinna)
3. Systemic:
   • ↓ Platelet, Hepatosplenomegaly, Transaminitis
   • Psoriasis, ILD (Interstitial Lung Disease) - Fibrosis, Episodic Worsening

Also Read: Primary Immunodeficiencies – Clinical Features, Investigations

AGS - In utero/Perinatal Presentation

• Mostly seen in AGS-1 (TREX-1 mutation)
• Pseudo-TORCH Complex:
  • IUGR, Microcephaly, Feeding difficulties
  • Seizures, ↓ Platelet, ↓ Hb, ↑ Liver Enzymes
  • Mortality: 30 to 50% in the first year of life
  • Virtually all have serious neuro sequelae

Neuroimaging Abnormalities

• Occur in both Classical and In-utero cases
• Includes:
  • Diffuse white matter abnormalities
  • Intracranial calcification (Most common site: Basal Ganglia/Striatum)
  • Cerebral Atrophy
  • Transient swelling in Frontal/Temporal lobes
  • If CSF done: Pleocytosis (+) and ↑ IFN Type 1 levels

Sequelae/Future Risk

• Development Delay
• Epilepsy
• Autoimmunity: Type 1 Diabetes Mellitus (T1DM) (1st decade)
• Hypothyroidism
• Hypergammaglobulinemia
• Hemolytic Anemia

Spondyloenchondrodysplasia (SPENCD) 

• Inheritance: Autosomal Recessive (AR)
• Gene: ACP5 gene on Chromosome 19p13, codes for TRAP (Tartrate-Resistant Acid Phosphatase)
• Pathophysiology:
  • Absence of TRAP protein leads to decreased inactivation of Osteopontin (Opn). This will lead to ↑ Osteopontin causing Bony Changes and ↑ IFN α production 

Clinical Manifestations of Spondyloenchondrodysplasia (SPENCD)

Skeletal Dysplasia

• Osteosclerosis
• Short Stature 
• Enchondromas
• Platyspondyly
• Irregular defects in Vertebral End Plates

Other Manifestations

• Spasticity
• I/C Calcification
• SLE-like (Cytopenias, Malar Rash, ANA+) 
• Hypothyroidism
• Raynaud’s Phenomenon
• Adult: Sjogren syndrome, Vitiligo

Also Read: Image Based Questions On Immune System

STING-Associated Vasculopathy with Onset in Infancy (SAVI)

• Inheritance: AD
• Gene: TMEM173
• Pathophysiology: Gain of function mutations in TMEM 173.

Clinical Manifestations

• Vasculopathy: Skin rash
  • Violaceous nodules or plaques: Face, ear, nose
  • Can progress to necrosis
• Pulmonary involvement: ILD (Interstitial Lung Disease), Asymptomatic LAP (Lymphadenopathy), Paratracheal Lung Fibrosis
• Other: Arthritis, Myositis, Oral ulcers, Nasal septal perforation
• Many of these children are: ANA+, Anti-cardiolipin, Anti-β2 GP1, cANCA

CANDLE Syndrome

• CANDLE: Chronic Atypical Neutrophilic Dermatosis Lipodystrophy Elevated Temperature
• Inheritance: AR > AD
• Gene: PSMB-8 gene, it codes for Proteasome β5i subunit
• Pathophysiology: Decrease in Proteasome function leading to Damaged protein accumulation causing
  • Cellular stress
  • Increased Type I IFN (interferon alpha)

Key Features

• Fever
• Skin: Neutrophilic dermatosis, Erythema Nodosum (EN)-like panniculitis, Annular erythema
• Lipodystrophy: Face, trunk
• Joint: Arthritis in the first decade, contractures in adults
• Rare: AIHA (Autoimmune Hemolytic Anemia) & Hypothyroidism

ISG15/USP18 Deficiency

• ISG15: IFN Stimulated Gene 15
• USP18: Ubiquitin-like Protein 18
• Produce AGS-like phenotype, especially seizures, intracranial calcification, and fever

Singleton-Merten Syndrome

• AD (Autosomal Dominant)
• Increased profile of the RIG-1 pathway (Retinoic Acid Inducible Gene-1)
• Increased Type I IFN expression
• Hallmarks:
  • Aortic valve calcification
  • Glaucoma
  • Osteoporosis in children

X-linked Reticulate Pigmentary Disorder

• Inheritance: XLD (X-linked dominant), more severe in males than females
• Involves POLA1 gene mutation → DNA POL-A enzyme
• Upregulation of Type I IFN pathway
• Clinical Features:
  • Diffuse skin pigmentation
  • Recurrent pneumonia, bronchiectasis
  • Failure to thrive (FTT), diarrhea, hypohidrosis
  • Urethral strictures

DNAse II Deficiency

• Normally degrades lysosomal DNA
• Inheritance: Autosomal Recessive (AR)
• SLE-like syndrome
  • Rash, chilblains, cytopenias, Raynaud's phenomenon, hepatosplenomegaly (HSM)
  • On investigation: ANA+, Anti-dsDNA+

Also Read: National Immunization Schedule

Autoimmune Interferonopathies

• Monogenic forms of SLE
  • SLE variants due to loss of function in DNAse II, DNASE1L3, and DNASE1
  • Present with typical SLE manifestations, including cytopenias
• Juvenile Dermatomyositis (JDM)
  • An elevated interferon (IFN) signature has been reported in JDM patients as well

Treatment Strategies in IFNopathies

• 1^st Line: Small molecule JAK inhibitors (Jakinibs)
  • Tofacitinib (JAK1/JAK3 inhibitor)
  • Banicitinib (JAK1/JAK2 inhibitor)
  • Ruxolitinib (JAK1/JAK2 inhibitor)
• Other treatment strategies: Some success with ART (Antiretroviral therapy) with Zidovudine and Abacavir for 12 months
• Upcoming therapy: Monoclonal antibody therapies
  • Anti-IFNα: Sifalimumab 
  • Anti-IFNAR: Anifrolumab

Key Points to Note

• Bilateral Striatal Necrosis and Severe Dystonia → AGS-6 (ADAR-1 mutation)
• Variable presentation in the form of Mouth Ulcers, Deforming Arthropathy, Cerebral Vasculopathy (causes early-onset Stroke), Glaucoma → AGS-5 (SAMHD-1 mutation)
• Spastic Paraparesis → AGS-2, AGS-6, AGS-7

Also Read: Key Points And Recommendations In Pediatric Advanced Life Support

Hope you found this blog helpful for your NEET SS Pediatrics Immunology and Vaccines preparation. For more informative and interesting posts like these, keep reading PrepLadder’s blogs.