Human neurotrophic polyomavirus JCV is considered the most important cause of diffuse demyelinating disease, such as PML . This virus is first transmitted through the nose and mouth and then transmitted to the bone marrow and kidneys through infected lymphocytes . Under these conditions, the virus can remain in the latent phase for many years. It is clear that, under the conditions of dysfunction of the immune system, the invading virus increasingly causes uncontrolled infection throughout the body.
Although the exact mechanism of the immune response to JCV is still unclear, a review of the 26 cases of PID associated with PML helps solve this complex puzzle. For example, a report of four cases with PML who had gain-of-function (GOF) mutations in STAT-1 revealed the major role of STAT-1 in controlling interferon (IFN) responses. Accordingly, it can be concluded that IFNs, especially gamma interferon (IFN-γ), play a significant role in controlling JCV . As another hypothesis in patients with GOF mutations in STAT-1, increased expression of programmed cell death protein ligand 1 (PD-L1) on T cells leads to anergy and dysfunction of these cells, which in turn predisposes to PML . The association of disorders such as DOCK8 deficiency  and hyper-IgE syndrome  with PML suggests a possible role for IL-17 in controlling the virus in normal individuals. Our report regarding the first PML case with RAC2 deficiency mutation provoked us to investigate the possible roles of this gene in the response of the immune system to JCV. RAC2 protein, as a member of the Rho GTPase family, plays a key role in the regulation of the cellular process of neutrophils in the activity of cytoskeleton actin dynamics, chemotaxis of neutrophils, cell migration, and NADPH oxidase activity .
Although our patient and his sibling had no symptoms in favor of neutrophil dysfunction despite having mutations in the same gene during infancy, the first manifestations at older ages can be attributed to their hypogammaglobulinemia, which suggests a significant role of the RAC2 gene in the development and activation of B and T cells. In the sample that was taken from the patient, a decrease in chemotaxis, as well as in the number and morphology of granules in neutrophils, confirmed serious dysfunction in these cells, but the patient did not have a specific manifestation in favor of neutrophil disorder. Nevertheless, immunophenotyping of lymphocytes in the patient indicated B-cell lymphopenia and abnormalities in T-cell subpopulations, with reversed ratio of CD4/CD8 T cells, decreased percentages of naive CD4, and CD8 T cells, and regulatory T and recent thymic emigrant cells . Therefore, it may be concluded that the patient had a combined disorder of B cells and T cells, which predisposed him to reactivation of latent JCV infection and PML. Cellular immunity plays a very important role in controlling JCV infection. The role of humoral immunity is not exactly known; in the patient of the current study, PCR for JCV was performed on a sample taken from CSF to confirm the diagnosis of PML .
Regarding PML treatment, it is important to pay attention to a few general strategies after making a correct and timely diagnosis. The first point is to prevent the virus from entering the cells, and the next point is to improve the immune response against the virus and treat predisposing underlying diseases. In the reported patient, with the aim of improving the immune response, firstly, the dose of IVIG was increased. The measured IgG level of the patient was reported to be 1058 mg/dL during hospitalization. Secondly, mirtazapine was used as an antiviral drug to block one of the virus receptors (5HTR2) in the host cells. Pembrolizumab as a PD-L1 inhibitor was another option in the treatment of the patient, although, unfortunately, owing to the high cost, despite the great efforts of the family and medical staff, it was not possible to prepare and prescribe this drug for the patient. Our patient did not respond to any of the treatments and suffered from the progression of neurological symptoms, and eventually died.