SUMMARY

 

1.  Mutations in IL-10 and IL-10 receptor have been reported in patients with inflammatory bowel disease. 

 

2.  Patients have severe early onset inflammatory bowel disease during the first year of life.  

 

3.  Complications include anal fissures and fistulae as well as abscess formation.  Patients commonly require surgical interventions including partial or total colectomy. 

 

4.  Inflammation is typically unresponsive to immunosuppressive therapies (corticosteroids, methotrexate, anti-TNFalpha).

 

5.  IL-10 is a critical anti-inflammatory cytokine secreted by immune cells, epithelial cells, and keratinocytes.  IL-10 acts to limit secretion of pro-inflammatory cytokines including TNF-alpha, IL-1, IL-6, and IL-12. 

 

6.  IL-10 and IL-10 receptor gene sequencing can confirm the diagnosis. 

 

7.  Hematopoietic stem cell transplantation (HSCT) has been successful in a small number of patients with IL-10 and IL-10 receptor deficiency.   

 

 

 

                                                                                                               

OVERVIEW

     

      IL-10 is a critical anti-inflammatory cytokine secreted by immune cells (monocytes, macrophages, dendritic cells, T cells, and B cells), epithelial cells, keratinocytes, and mast cells.  IL-10 acts to limit secretion of pro-inflammatory cytokines including TNF-alpha, IL-1, IL-6, and IL-12.  The inhibition of pro-inflammatory cytokines prevents excessive immune responses that result in tissue damage.  

 

     Mutations in IL-10 and IL-10 receptor have been reported in patients with severe early onset intractable inflammatory bowel disease.  Biopsies reveal inflammatory infiltrates, ulcerations and abscesses.   Complications include anal fissures and fistulae as well as abscess formation.  Patients commonly require surgical interventions including partial or total colectomy. 

 

     The differential diagnosis for early onset enteropathy also includes Wiskott-Aldrich Syndrome (WAS), chronic granulomatous diasease, NEMO deficiency, XIAP deficiency, IPEX syndrome, CD25 deficiency, STAT1 (gain of function) mutations, omen syndrome, and dyskeratosis congenita.  

     

 

                                  

EVALUATION

 

Step 1:  Immune Evaluation

 

-CBC with Differential
-IgG, IgM, IgA, IgE
-Specific antibody responses to vaccine antigens
-Lymphocyte flow cytometry (including naïve/memory T cells)
-DHR assay

 

-A CBC with differential can help screen for Wiskott-Aldrich Syndrome (WAS) (thrombocytopenia and small platelet size).  Patients with Omenn, WAS, IPEX can have eosinophilia.  

-IgG, IgA, IgM, IgE levels are typically normal in patients with IL-10/IL-10R deficiency. Elevated IgE can be present in Omenn syndrome, WAS and IPEX. 

-Specific antibody responses can be reduced in WAS, NEMO deficiency. 

-T cell lymphocytopenia can be present in WAS, CD25 deficiency.  Patients with dyskeratosis congenita typically have a T+B-NK- phenotype.  Patients with Omenn syndrome can have normal or elevated T cells (due to oligoclonal expansion) but the T cells have a memory (CD45RO) phenotype rather than a naïve (CD45RA) phenotype. 

-A DHR assay is an excellent screen for chronic granulomatous disease. 


Step 2:  IL-10R Functional Screen

 

-A functional screen for IL-10R can be performed by stimulation with IL-10 followed by measurement of STAT3 phosphorylation.  

 

-This test is commercially available through Seattle Children’s Immunology Diagnostic Laboratory


Step 3:  IL-10R Gene Sequencing


-IL-10R gene sequencing (IL10RA/IL10RB)


-Genetic testing for IL10RA and IL10RB mutations is commercially available through Seattle Children’s Immunology Diagnostic Laboratory

 

 

                                                                  

MANAGEMENT

        

           Patients with IL10 and IL10R gene mutations are unresponsive to immunosuppressive therapies (corticosteroids, methotrexate, anti-TNFalpha). Hematopoietic stem cell transplantation (HSCT) has been successful in a small number of patients with IL-10 and IL-10 receptor deficiency, suggesting this may be a viable treatment options for patients with refractory disease.    

 

 

 

                                                                           

RESOURCES

Literature Resources

 

1. Glocker 2011

    IL10 & IL10R (Review)

 

2. Glocker 2009

    IL10 Receptor Deficiency and IBD

 

3. Engelhardt 2013

    HSCT in IL10 & IL10R Deficiency