Griscelli syndrome (GS, MIM 214450), a rare, autosomal recessive disorder, results in pigmentary dilution of the skin and the hair, the presence of large clumps of pigment in hair shafts and an accumulation of melanosomes in melanocytes. Most patients also develop an uncontrolled T-lymphocyte and macrophage activation syndrome (known as haemophagocytic syndrome, HS), leading to death in the absence of bone-marrow transplantation. In contrast, early in life some GS patients show a severe neurological impairment without apparent immune abnormalities. We previously mapped the GS locus to chromosome 15q21 and found a mutation in a gene (MYO5A) encoding a molecular motor in two patients. Further linkage analysis suggested a second gene associated with GS was in the same chromosomal region. Homozygosity mapping in additional families narrowed the candidate region to a 3.1-cM interval between D15S1003 and D15S962. We detected mutations in RAB27A, which lies within this interval, in 16 patients with GS. Unlike MYO5A, the GTP-binding protein RAB27A appears to be involved in the control of the immune system, as all patients with RAB27A mutations, but none with the MYO5A mutation, developed HS. In addition, RAB27A-deficient T cells exhibited reduced cytotoxicity and cytolytic granule exocytosis, whereas MYO5A-defective T cells did not. RAB27A appears to be a key effector of cytotoxic granule exocytosis, a pathway essential for immune homeostasis.

Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition of severe hyperinflammation caused by the uncontrolled proliferation of activated lymphocytes and histiocytes secreting high amounts of inflammatory cytokines. Cardinal signs and symptoms are prolonged fever, hepatosplenomegaly and pancytopenia. Characteristic biochemical markers include elevated triglycerides, ferritin and low fibrinogen. HLH occurs on the basis of various inherited or acquired immune deficiencies. Impaired function of natural killer (NK) cells and cytotoxic T-cells (CTL) is shared by all forms of HLH. Genetic HLH occurs in familial forms (FHLH) in which HLH is the primary and only manifestation, and in association with the immune deficiencies Chediak-Higashi syndrome 1 (CHS 1), Griscelli syndrome 2 (GS 2) and x-linked lymphoproliferative syndrome (XLP), in which HLH is a sporadic event. Most patients with acquired HLH have no known underlying immune deficiency. Both acquired and genetic forms are triggered by infections, mostly viral, or other stimuli. HLH also occurs as a complication of rheumatic diseases (macrophage activation syndrome) and of malignancies. Several genetic defects causing FHLH have recently been discovered and have elucidated the pathophysiology of HLH. The immediate aim of therapy in genetic and acquired HLH is suppression of the severe hyperinflammation, which can be achieved with immunosuppressive/immunomodulatary agents and cytostatic drugs. Patients with genetic forms have to undergo stem cell transplantation to exchange the defective immune system with normally functioning immune effector cells. In conclusion, awareness of the clinical symptoms and of the diagnostic criteria of HLH is crucial in order not to overlook HLH and to start life-saving therapy in time.

Familial and acquired hemophagocytic lymphohistiocytosis

The natural killer (NK)-cell immunological synapse is the dynamic interface formed between an NK cell and its target cell Formation of the NK-cell immunological synapse involves several distinct stages, from the initiation of contact with a target cell to the directed delivery of lytic-granule contents for target-cell lysis Progression through the individual stages is regulated, and this tight regulation underlies the precision with which NK cells select and kill susceptible target cells (including virally infected cells and cancerous cells) that they encounter during their routine surveillance of the body

/pdf/formation-and-function-of-the-lytic-nk-cell-immunological-4hd9x9nsw2.pdf

Formation and function of the lytic NK-cell immunological synapse

https://www.cell.com/trends/molecular-medicine/pdf/S1471-4914(01)02227-4.pdf

Rab GTPases, intracellular traffic and disease.

Griscelli disease (OMIM 214450) is a rare autosomal recessive disorder characterized by pigmentary dilution, variable cellular immunodeficiency and onset of acute phases of uncontrolled lymphocyte and macrophage activation, leading to death in the absence of bone-marrow transplantation. The pigmentary dilution is characterized by a diffuse skin pigmentation, silvery hair, large clumps of pigments in the hair shafts (Fig. 1) and an accumulation of melanosomes in melanocytes, with abnormal transfer of the melanin granules to the keratinocytes. Immunological abnormalities are characterized by absent delayed-type cutaneous hypersensitivity and an impaired natural-killer cell function. A similar disorder has been described in the dilute lethal mouse--which, however, differs by the occurrence of a severe neurological disorder. The dilute locus encodes myosin-Va, a member of the unconventional myosin family. Myosins bind actin and produce mechanical force through ATP hydrolysis. Some members of this family are thought to participate in organelle-transport machinery. Because of the phenotype resulting in the dilute mouse and because of their potential role in intracellular transport, unconventional myosin-encoding genes were regarded as candidate genes for Griscelli disease. Here we report that the Griscelli disease locus co-localizes on chromosome 15q21 with the myosin-Va gene, MYO5a, and that mutations of this gene occur in two patients with the disease. Griscelli disease is therefore a human equivalent of dilute expression in the mouse.

Griscelli Disease Maps to Chromosome 15q21 and Is Associated With Mutations in the myosin-Va Gene

Partial albinism with immunodeficiency (Griscelli syndrome)

RESULTS: Production of IL10 in response to bacterial motifs was normal in all IBD patients. In contrast to our original hypothesis, no defect of the anti-infl ammatory potential of TGF and IL10 was observed in children with IBD or EO-IBD except two infants who presented with granuloma-posi- tive colitis at 3 months of life: no response to IL10 was observed secondary to mutations in the (p.R262C) or (p.E141X) chain of IL10R, respectively, although a fully functional Jak-STAT3 pathway was present in both patients. When analyzing the regulation of intestinal bacterial clear- ance, we detected a defect in the patient with absent IL10 RB to upregulate protective transcripts in response to IL22, whereas all other EO-IBD patients, including the patient with an abnormal chain, responded normally. CONCLUSIONS: Impaired IL10 signaling characterizes a subgroup of IBD patients, whereas the majority of children with severe IBD including EO forms normally produces and responds to IL10. Defective IL22 signal- ing may additionally impair intestinal epithelial clearance. Our data point out the complexity of IBD, which represent a group of distinct diseases with several pathogenetic abnormalities.

Christoph Klein

Papers

Partial albinism with immunodeficiency (Griscelli syndrome)

Defective IL10 Signaling Defi ning a Subgroup of Patients With Infl ammatory Bowel Disease