WHIM syndrome

The WHIM syndrome (short for warts - hypogammaglobulinemia immunodeficiency Myelokathexis syndrome) is an inherited, rare immunodeficiency disease.

History

The common occurrence of the characteristic symptoms of the WHIM syndrome was first described in 1964. In 2000, the genetic cause of this syndrome could be found. WHIM syndrome which is the first immune defect is due to a Zytokinrezeptordefekt.

Symptoms

Characteristic of the WHIM syndrome is an immunodeficiency that manifests itself in recurrent bacterial and viral infections. Of the respiratory tract with sinusitis, tonsillitis and pneumonia are especially affected. The patients are susceptible to infection with human papillomavirus, which manifest themselves in numerous warts, particularly in the hand and foot. WHIM syndrome patients also have an increased risk of developing viral- related cancers, such as the cervix. In the blood serum of patients decreased IgG concentrations can be measured ( hypogammaglobulinemia ). Histologically, the bone marrow of WHIM patients full of T -cell progenitors appear. On the other hand, a neutropenia are observed which can be attributed to an impaired emigration and thus restraint of neutrophils from the bone marrow ( Myelokathexis ).

Causes

The WHIM syndrome is an autosomal dominant inherited disease. The most common cause of which was found in 92% of affected patients, mutations of a gene on the 2q21 locus encoding the chemokine receptor CXCR4 considered. These mutations in the intracellular portion of the membrane-bound receptor for the cytokine CXCL12 (SDF -1) lead to a truncated receptor protein that lacks the ability of internalization after activation. Thus, mechanisms of negative self-regulation are interrupted and the receptor can be dauerstimuliert. A reduction of the expression of CXCR4 is also a prerequisite for the exit of T- progenitor cells from the bone marrow. Due to the mutation and the lack of internalization of CXCR4 remain on the surface of the TC - precursor cells. These progenitor cells may therefore not leave the bone marrow and are the cause of the histological findings in the bone marrow and blood.

The WHIM syndrome, however, can be observed sporadically in patients ( 8% of patients) with a non- mutated (wild-type ) CXCR4. One possible cause in these patients is a malfunction of proteins that are involved in the internalization of CXCR4, such as GRKs.

As the CXCR4 receptor in other migration and Homingprozessen plays a role in the immune system is impaired in the periphery.

Therapy

In the treatment of patients with a WHIM syndrome is the reduction of susceptibility to infection in the foreground. Substitution with immunoglobulins to reduce the incidence of infection. To normalize the release of neutrophil granulocytes from the bone marrow, GM- CSF or G- CSF better be used. The use of CXCR4 antagonists, such as plerixafor, for the treatment of patients with WHIM syndrome is currently being investigated in clinical trials.