Loss of intrahepatic bile ducts: an important feature of familial hemophagocytic lymphohistiocytosis

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare, fatal disorder of early infancy. We report two siblings with FHL whose symptoms were dominated by hepatic failure. Both presented with sudden-onset fever and hepatosplenomegaly with progressive abnormalities of clinical biochemistry indices of liver function. One died of hepatorenal failure. The other underwent liver transplantation. Autopsy and explant liver displayed portal and periportal infiltrates of T lymphocytes and histiocytes; an activation of the hepatic mononuclear phagocytic system with focal hemophagocytosis; and almost complete loss of interlobular bile ducts. Paucity of bile ducts dominated in a pre-transplant liver biopsy specimen (and transiently obscured the diagnosis of FHL). Disease recurred in the allograft, again with lymphohistiocytic infiltration and destruction of interlobular bile ducts. Consequently the patient underwent haploidentical peripheral stem cell transplantation. This patient is alive 5 years later. Loss of bile ducts may be an important feature of hepatic involvement by FHL.     

Phenotypic heterogeneity in British patients with a founder mutation in the FHL1 gene

Mutations in the four-and-a-half LIM domain 1 (FHL1) gene, which encodes a 280-amino-acid protein containing four LIM domains and a single zinc-finger domain in the N-terminal region, have been associated with a broad clinical spectrum of X-linked muscle diseases encompassing a variety of different phenotypes. Patients might present with a scapuloperoneal myopathy, a myopathy with postural muscle atrophy and generalized hypertrophy, an Emery-Dreifuss muscular dystrophy, or an early onset myopathy with reducing bodies. It has been proposed that the phenotypic variability is related to the position of the mutation within the FHL1 gene. Here, we report on three British families with a heterogeneous clinical presentation segregating a single FHL1 gene mutation and haplotype, suggesting that this represents a founder mutation. The underlying FHL1 gene mutation was detected by direct sequencing and the founder effect was verified by haplotype analysis of the FHL1 gene locus. A 3-bp insertion mutation (p.Phe127_Thr128insIle) within the second LIM domain of the FHL1 gene was identified in all available affected family members of the three families. Haplotype analysis of the FHL1 region on Xq26 revealed that the families shared a common haplotype. The p.Phe127_Thr128insIle mutation in the FHL1 gene therefore appears to be a British founder mutation and FHL1 gene screening, in particular of exon 6, should therefore be indicated in British patients with a broad phenotypic spectrum of X-linked muscle diseases.     

Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare autosomal recessive disorder characterized by hyperactive phagocytes and defects in natural killer cell function. It has been shown previously that mutations in the perforin 1 gene (PRF1) and in UNC13D are associated with FHL2 and FHL3, respectively, indicating genetic heterogeneity. We performed genome-wide homozygosity mapping in a large consanguineous Kurdish kindred with five children affected with FHL. Linkage to a 10 cM region on chromosome 6q24 between D6S1569 and D6S960 defined a novel FHL locus. By screening positional candidate genes, we identified a homozygous deletion of 5 bp in the syntaxin 11 gene (STX11) in this family. We could demonstrate that syntaxin 11 protein was absent in the mononuclear cell fraction of patients with the homozygous 5 bp deletion. In addition to this family, we found homozygous mutations in STX11 in five consanguineous Turkish/Kurdish FHL kindreds including two families with the 5 bp deletion, one family with a large 19.2 kb genomic deletion spanning the entire coding region of STX11 (exon 2) and two families with a nonsense mutation that leads to a premature stop codon in the C-terminal end of the protein. As both STX11 and UNC13D are involved in vesicle trafficking and membrane fusion, we conclude that, besides mutations in perforin 1, defects in the endocytotic or the exocytotic pathway may be a common mechanism in FHL.     

FHL2 expression in peritumoural fibroblasts correlates with lymphatic metastasis in sporadic but not in HNPCC-associated colon cancer

Four and a half LIM domain protein-2 (FHL2) is a component of the focal adhesion structures and has been suggested to have an important role in cancer progression. This study analyses the role of FHL2 in peritumoural fibroblasts of sporadic and hereditary non-polyposis colorectal cancer (HNPCC). Tissue specimens of 48 sporadic and 49 hereditary colon cancers, respectively, were stained immunohistochemically for FHL2, transforming growth factor (TGF)-β1 ligand and α-SMA. Myofibroblasts at the tumour invasion front co-expressed α-SMA and FHL2. Sporadic colon cancer but not HNPCC cases showed a correlation between TGF-β1 expression of the invading tumour cells and FHL2 staining of peritumoural myofibroblasts. Overexpression of FHL2 in peritumoural myofibroblasts correlated to lymphatic metastasis in sporadic colon cancer but not in HNPCC. In cultured mouse fibroblasts, TGF-β1 treatment induced myofibroblast differentiation, stimulated FHL2 protein expression and elevated number of migratory cells in transwell motility assays, suggesting that FHL2 is regulated downstream of TGF-β. Physical contact of colon cancer cells and myofibroblasts via FHL2-positive focal adhesions was detected in human colon carcinoma tissue and in co-culture assays using sporadic as well as HNPCC-derived tumour cell lines. Our data provide strong evidence for an important role of FHL2 in the progression of colon cancers. Tumour-secreted TGF-β1 stimulates FHL2 protein expression in peritumoural fibroblasts, probably facilitating the invasion of tumour glands into the surrounding tissue by enhanced myofibroblast migration and tight connection of fibroblasts to tumour cells via focal adhesions. These findings are absent in HNPCC-associated colon cancers in vivo and may contribute to a less invasive and more protruding tumour margin of microsatellite instable carcinomas.     

Follicular hodgkin lymphoma: a histopathologic study.

Follicular Hodgkin lymphoma (FHL) is a form of classic Hodgkin lymphoma with morphologic similarity to nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). We present the clinicopathologic features of 13 FHL cases and compare their morphologic features with 40 cases of NLPHL. Seven males and 6 females had FHL in the lymph nodes of the neck (6 patients), axilla (3 patients), groin (2 patients), and mediastinum (1 patient) and in the nasopharynx (1 patient). All FHLs had follicles with small, eccentric germinal centers (GCs) and expanded mantle zones containing classic Reed-Sternberg (RS) cells; reactive GCs also were seen in 6 of 13 cases. The RS cells were CD30+, fascin+ in 13 cases; CD15+ in 11 cases; CD20+ in 4 cases; CD79alpha+CD20- in 1 case; and negative for epithelial membrane antigen in 12 cases; they were surrounded by CD3epsilon+ and CD57+ rosettes in 13 and 2 cases, respectively. Morphologically, FHL may closely simulate NLPHL, and, thus, immunohistochemical analysis is essential to confirm the diagnosis. Clues helpful in diagnosing FHL include the presence offollicles with GCs, classic RS cells, and a relative absence of histiocytes.     

An anatomic study of the quadratus plantae in relation to tendinous slips of the flexor hallucis longus for gait analysis

The aim of this study was to demonstrate the morphology of the quadratus plantae (QP) in relation to the tendinous slips of the flexor hallucis longus (FHL) and their surrounding structures, thereby providing data to understand function of the QP during gait, and for analyzing the movements of the foot and designing postoperative rehabilitation programs. The QP was investigated in 50 specimens of embalmed adult cadavers. The QP inserted into the tendon of the flexor digitorum longus (FDL) and the tendinous slips of the FHL in 96%, and only to the tendon of the FDL in 4%. The tendinous slip of the FHL targeted the tendon for the second toe in 4 of the 50 specimens (8%). The tendinous slip divided into two separate slips to the tendons for the second and third toes in 32 specimens (64%), and for the second, third, and fourth toes in 14 specimens (28%). Thus, the tendon and tendinous slips of the FHL may distribute the load of the great toe to the second toe to the third or fourth toe in the forefoot, especially during toe-off. In addition, the main attachment of the QP to the tendinous slips of the FHL may provide more efficient control of the long flexor tendons in comparison with that of the QP to the tendon of the FDL.     

Peripheral and central control of flexor digitorum longus and flexor hallucis longus motoneurons: The synaptic basis of functional diversity

Summary The two long toe flexor muscles in the cat, flexor digitorum longus (FDL) and flexor hallucis longus (FHL), have essentially identical mechanical actions, yet are used very differently during locomotion (O'Donovan et al. 1982). We attempted to identify the origin of the synaptic drive responsible for this functional differentiation.The organization of peripheral and central synaptic drive to FDL and FHL motoneurons was examined using two basic paradigms. (1) In animals anesthetized with chloralose or after ischemic destruction of the brain, peripheral reflex circuits were studied by recording intracellular responses from -motoneurons produced by electrical stimulation of muscular and cutaneous nerves. (2) Fictive locomotion, the centrally generated rhythmic synaptic drive produced in paralyzed, decerebrate animals by stimulation of the mesencephalic locomotor region or intravenous injection of L-DOPA and Nialamide, was monitored by recording electro-neurograms from the central end of cut motor nerves.Despite their functional dissimilarity, FDL and FHL motoneurons received monosynaptic EPSPs from both FDL and FHL la afferents. Ipsilateral cutaneous afferents in the sural nerve and from the central plantar pad produced multiphasic PSPs which were not different in FDL and FHL cells. However afferents from the saphenous and superficial peroneal nerves did exert differential effects: the first component of the multiphasic PSP in most FDL cells was an EPSP, which was not present in most FHL cells. The central latency of this early EPSP in FDL motoneurons (0.8–1.5 ms) strongly suggests a disynaptic linkage. Cutaneous afferents from the ipsilateral forelimb produced IPSPs in most FHL cells but in only one of 18 FDL cells. Since some peripheral reflex circuits exerted differential effects on FDL and FHL cells, but others did not, the intracellular data did not demonstrate that the functional differences between FDL and FHL could be explained by differences in reflex organization.During fictive locomotion elicited by electrical or pharmacological stimulation, FHL motoneurons were coactive with ankle extensors during the extension phase of the fictive step cycle. In contrast, FDL motoneurons were most consistently activated in a brief burst at the onset of the flexion phase, showing much weaker and more variable coactivity with ankle extensors. These patterns were essentially identical to those reported for FDL and FHL motor pools during treadmill locomotion by O'Donovan et al. (1982).We conclude that the central pattern generator (CPG) for locomotion produces distinct and highly differentiated sets of instructions for FDL and FHL motoneurons. Peripheral and descending systems are important in initiating and biasing the activity of the CPG, but are not responsible for the intrinsic structure of the locomotor command signals.     

LIM‐only protein FHL2 regulates experimental pulmonary Schistosoma mansoni egg granuloma formation

LIM‐only protein FHL2 is associated with several immune and inflammatory diseases such as arthritis, influenza A virus infection, and lung inflammation. However, the role of FHL2 in macrophage differentiation and in the development of granuloma formation is unknown. Here, we show that expression of FHL2 is induced in mouse bone marrow derived macrophages (BMMs) following stimulation with M2 cytokines such as IL‐4 and IL‐10. FHL2‐knockout (FHL2‐KO) BMMs exhibit a proinflammatory M1 phenotype after LPS treatment and display a reduced anti‐inflammatory M2 phenotype following IL‐4 treatment. Furthermore, thioglycollate‐induced migration of macrophages and B cells is enhanced in FHL2‐KO mice. To evaluate the importance of FHL2 in the development of pulmonary granuloma formation, FHL2‐KO mice were challenged with Schistosoma mansoni eggs. FHL2‐KO mice show an enhanced number of granulomas and display decreased expression of Th2 markers and an exacerbated Th1 type of inflammation, characterized by enhanced expression of neutrophil markers and Th1 cytokines. Furthermore, the expression of barrier proteins is reduced in FHL2‐KO lung compared to WT. Collectively, these data identify a previously unrecognized role for FHL2 in the pathogenesis of pulmonary granulomatous inflammation, partly through its effect on macrophage polarization, modulation of the Th1/Th2 balance and regulation of permeability in lung.     

Trigger-dependent differences determine therapeutic outcome in murine primary hemophagocytic lymphohistiocytosis

Familial hemophagocytic lymphohistiocytosis (FHL) is a hyperinflammatory syndrome affecting patients with genetic cytotoxicity defects. Perforin-deficient (PKO) mice recapitulate the full clinical picture of FHL after infection with lymphocytic choriomeningitis virus (LCMV). Hyperactivated CD8⁺ T cells and IFN-γ have been identified as the key drivers of FHL and represent targets for therapeutic interventions. However, the response of patients is variable. This could be due to trigger-dependent differences in pathogenesis, which is difficult to address in FHL patients, since the trigger frequently escapes detection. We established an alternative FHL model using intravenous infection of PKO mice with murine CMV (MCMV)_Smith. PKO mice developed acute FHL after both infections and fulfilled HLH diagnostic criteria accompanied by excessive IFN-γ production by disease-inducing T cells, that enrich in the BM. However, direct comparison of the two infection models disclosed trigger-dependence of FHL progression and revealed a higher contribution of CD4 T cells and NK cells to IFN-γ production after MCMV infection. Importantly, therapeutic intervention by IFN-γ neutralization or CD8⁺ T-cell depletion had less benefit in MCMV-triggered FHL compared to LCMV-triggered FHL, likely due to MCMV-induced cytopathology. Thus, the context of the specific triggering viral infection can impact the success of targeted immunotherapeutic HLH control.     

Chromosomal Mapping of a Skeletal Muscle Specific LIM-Only Protein FHL3 to the Distal End of the Short Arm of Human Chromosome 1

Four-and-a-half LIM domain proteins (FHL) possess four tandem repeats of LIM domain and an extra zinc finger. FHL family LIM proteins are unique when compared with other LIM-only proteins because they possess an odd number of zinc fingers. In this study, the tissue distribution and chromosomal mapping of skeletal muscle LIM protein FHL3 were reported. When the FHL3 cDNA probe was used to hybridize with poly-(A) RNA of various human tissues, a very strong signal was detected in skeletal muscle, and virtually no signal could be detected in heart, brain, placenta, lung, liver, kidney and pancreas. Using radiation hybrid technique, FHL3 gene was mapped to the distal end of the short arm of chromosome 1 (123.26 cR from the top of the Chr1 linkage group) and this region (near 1p34) is related to several human malignancies.     

Tonic and phasic discharge patterns in toe flexor gamma-motoneurons during locomotion in the decerebrate cat.

To investigate the specificity of fusimotor (gamma) drive during locomotion, gamma-efferents were recorded from the flexor digitorum longus (FDL) and flexor hallucis longus (FHL) nerves in a decerebrate cat preparation. These nerves innervate hindlimb muscles that differ in some aspects of their mechanical action. For both FHL and FDL two stereotyped patterns of gamma activity were distinguished. Tonic units fired throughout the step cycle and had less modulation, but higher minimum rates, than phasic units, which were mainly recruited with ankle extensor [soleus (SOL)] electromyogram (EMG) activity. Differences in the relative timing of these patterns were apparent. In FHL the activity of phasic and most tonic neurons peaked after EMG onset. With FDL, tonic units generally reached maximum rate before, while phasic units peaked after, the beginning of EMG activity. During locomotion FHL and FDL alpha activity were rhythmically recruited with SOL. However, consistent with previous reports, FHL and FDL differed in their patterns of alpha activity. FHL was stereotyped while FDL was variable. Both FHL and FDL had activity related to ankle extensor EMG, but only FDL exhibited a peak around the end of this phase. No corresponding gamma activity was observed in FDL. In conclusion, 1) FHL and FDL received tonic and phasic fusimotor drive; 2) there was no alpha/gamma linkage for the late FDL alpha burst; 3) phasic gamma-efferents in both muscles received similar inputs, linked to plantar flexor alpha activity; and 4) tonic gamma-efferents differed, to the extent that they were modulated at all. The FHL units peaked with the plantar flexor alphas. The FDL neurons generally peaked before alpha activity even began.     

Functional health literacy and the quality of physician-patient communication among diabetes patients

While patients with poor functional health literacy (FHL) have difficulties reading and comprehending written medical instructions, it is not known whether these patients also experience problems with other modes of communication, such as face-to-face encounters with primary care physicians. We enrolled 408 English- and Spanish-speaking diabetes patients to examine whether patients with inadequate FHL report worse communication than patients with adequate FHL. We assessed patients' experiences of communication using sub-scales from the Interpersonal Processes of Care in Diverse Populations instrument. In multivariate models, patients with inadequate FHL, compared to patients with adequate FHL, were more likely to report worse communication in the domains of general clarity (adjusted odds ratio [AOR] 6.29, P<0.01), explanation of condition (AOR 4.85, P=0.03), and explanation of processes of care (AOR 2.70, p=0.03). Poor FHL appears to be a marker for oral communication problems, particularly in the technical, explanatory domains of clinician-patient dialogue. Research is needed to identify strategies to improve communication for this group of patients.     

FHL1在香烟烟雾刺激的大鼠肺动脉平滑肌细胞增殖与迁移中的作用

 目的：研究FHL1 (four-and-a-half LIM domain 1)在香烟烟雾提取物（CSE）刺激的大鼠远端肺动脉平滑肌细胞（PASMCs）增殖及迁移中的作用。方法：原代培养PASMCs,分别予CSE及FHL1 siRNA转染干预,分为6组：空白组、阴性转染组、FHL1 siRNA转染组、CSE组、CSE+阴性转染组和CSE+FHL1 siRNA转染组。Real-time PCR法检测FHL1 mRNA的表达,Western blotting法检测FHL1 蛋白,CCK-8法检测细胞增殖,Transwell 法测定细胞迁移。结果：CSE刺激导致PASMCs增殖、迁移及FHL1蛋白表达增加 (P<0.01) ,但FHL1 mRNA的表达无明显改变（P＞0.05）。FHL1 siRNA转染PASMCs,可降低CSE所致的PASMCs增殖及迁移(P<0.01)。结论：CSE可促进PASMCs增殖与迁移以及FHL1蛋白的表达, 抑制FHL1蛋白的表达可减弱CSE对PASMCs增殖和迁移的作用。这些结果表明CSE促进PASMCs增殖和迁移与FHL1蛋白有关。     

Evidence for FHL1 as a novel disease gene for isolated hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric left ventricular hypertrophy, diastolic dysfunction and myocardial disarray. HCM is caused by mutations in sarcomeric genes, but in >40% of patients, the mutation is not yet identified. We hypothesized that FHL1, encoding four-and-a-half-LIM domains 1, could be another disease gene since it has been shown to cause distinct myopathies, sometimes associated with cardiomyopathy. We evaluated 121 HCM patients, devoid of a mutation in known disease genes. We identified three novel variants in FHL1 (c.134delA/K45Sfs, c.459C>A/C153X and c.827G>C/C276S). Whereas the c.459C>A variant was associated with muscle weakness in some patients, the c.134delA and c.827G>C variants were associated with isolated HCM. Gene transfer of the latter variants in C2C12 myoblasts and cardiac myocytes revealed reduced levels of FHL1 mutant proteins, which could be rescued by proteasome inhibition. Contractility measurements after adeno-associated virus transduction in rat-engineered heart tissue (EHT) showed: (i) higher and lower forces of contraction with K45Sfs and C276S, respectively, and (ii) prolonged contraction and relaxation with both mutants. All mutants except one activated the fetal hypertrophic gene program in EHT. In conclusion, this study provides evidence for FHL1 to be a novel gene for isolated HCM. These data, together with previous findings of proteasome impairment in HCM, suggest that FHL1 mutant proteins may act as poison peptides, leading to hypertrophy, diastolic dysfunction and/or altered contractility, all features of HCM.     

Up-regulated FHL1 Expression Maybe Involved in the Prognosis of Hirschsprung's Disease

Background: In a subset of patients with Hirschsprung''s disease (HSCR), gastrointestinal motor dysfunction persisted long after surgical correction. Gastrointestinal motility is achieved through the coordinated activity of the enteric nervous system, interstitial cells of Cajal, and smooth muscle (SMC) cells. Inhibition of four-and-a-half LIM protein-1 (Fhl1) expression by siRNA significantly decreases pulmonary artery SMCs migration and proliferation. Furthermore when up-expressing FHL1 in atrial myocytes, K (+) current density markedly increases, therefore changing myocytes'' response to an electrical stimulus. However whether FHL1 in colon SMCs (the final effector organ) influences intestinal motility in HSCR patients has not been clarified. Methods: FHL1 mRNA and protein expressions were analyzed in 32 HSCR colons and 4 normal colons. Results: Smooth muscle layers were thicken and disorganized in HSCR. FHL1 was expressed in the ganglion cells of the myenteric plexus, submucosa, as well as in the longitudinal and circular muscle layer of the ganglionic colon. FHL1 mRNA relative expression level in aganglionic colons was 1.06±0.49 (ganglionic colon relative expression level was 1) (P=0.44). FHL1 protein gray level relative to GAPDH in normal colons was 0.83±0.09. FHL1 expression level in ganglionic colon (1.66±0.30) or aganglionic colon (1.81±0.35) was significantly higher than that in normal colons (P=0.045 and P=0.041, respectively). Meanwhile, we found FHL1 expression in aganglionic colon was slightly stronger than that in ganglionic colon (P=0.036). Conclusion: These data suggested that up-regulated FHL1 in smooth muscle in HSCR might be associated with intestinal wall remodeling in HSCR and might be one of the risk factors for gastrointestinal motor dysfunction.     

Muscle hypertrophy as the presenting sign in a patient with a complete FHL1 deletion

Four and a half LIM protein 1 (FHL1/SLIM1) has recently been identified as the causative gene mutated in four distinct diseases affecting skeletal muscle that have overlapping features, including reducing body myopathy, X‐linked myopathy, X‐linked dominant scapuloperoneal myopathy and Emery–Dreifuss muscular dystrophy. FHL1 localises to the sarcomere and the sarcolemma and is believed to participate in muscle growth and differentiation as well as in sarcomere assembly. We describe in this case report a boy with a deletion of the entire FHL1 gene who is now 15 years of age and presented with muscle hypertrophy, reduced subcutaneous fat, rigid spine and short stature. This case is the first, to our knowledge, with a complete loss of the FHL1 protein and MAP7D3 in combination. It supports the theory that dominant negative effects (accumulation of cytotoxic‐mutated FHL1 protein) worsen the pathogenesis. It extends the phenotype of FHL1‐related myopathies and should prompt future testing in undiagnosed patients who present with unexplained muscle hypertrophy, contractures and rigid spine, particularly if male.     

Mutations of syntaxin 11 and SNAP23 genes as causes of familial hemophagocytic lymphohistiocytosis were not found in Japanese people

Although mutations of perforin, MUNC13-4 and syntaxin 11 genes have been found in children with familial hemophagocytic lymphohistiocytosis (FHL), the incidence of each genetic subtype varies in different ethnic groups. We evaluated mutations of syntaxin 11 and SNAP23 genes in 30 Japanese FHL patients. The patients had no mutations and 10% had one polymorphism (146G>A) of syntaxin 11, while no mutation of SNAP23 was observed. Our results indicate that aberrations in the SNARE system may not cause FHL in Japanese families.     

Recurrent collaterals of motoneurons projecting to distal muscles in the cat hindlimb.

1. Recurrent collaterals of motoneurons innervating muscles that have a role in control of the hindlimb digits were studied with neuroanatomic tracing methods to determine whether these motoneurons have simple recurrent collateral arbors in comparison with those of hip, knee, and ankle muscles. 2. Motoneurons innervating the hindlimb muscles plantaris (Pln), flexor hallucis longus (FHL), or flexor digitorum longus (FDL) were injected with 10% horseradish peroxidase. Recurrent collaterals were reconstructed from serial transverse sections. 3. No recurrent collaterals were observed in a sample of 10 FDL motoneurons. 4. FHL motoneurons had simple recurrent collateral arbors as assessed by number of first-order collaterals, number of collateral swellings, number of end branches, and the highest-order branch of individual collateral trees. Recurrent collateral arbors of Pln motoneurons were more complex than those of FHL motoneurons. Pln and FHL recurrent collateral arbors were less complex than those described for gastrocnemius-soleus, anterior tibial, and posterior biceps motoneurons. 5. These anatomic findings correspond well with electrophysiological results indicating that the recurrent inhibition produced by FHL motoneurons is weak and that FDL motoneurons do not produce recurrent inhibition. In addition, Pln motoneurons are reported to produce stronger recurrent inhibition than FHL motoneurons in many motor pools. 6. Consideration of these results with respect to the mechanical actions and patterns of motor activity observed in FDL, FHL, and Pln suggests that the complexity of recurrent collaterals of a motoneuron pool and the extent of its contribution to recurrent inhibition diminish with its involvement in the individualized control of the digits.     

Down-regulation of CD5 expression on activated CD8 T cells in familial hemophagocytic lymphohistiocytosis with perforin gene mutations

Hemophagocytic lymphohistiocytosis (HLH) is characterized by uncontrolled activation of T cells and macrophages with overproduction of cytokines. Familial HLH type 2 (FHL2) is the most common form of primary HLH and is caused by mutations in PRF1. We have recently described a significant increase in the subpopulation of CD8⁺ T cells with clonal expansion and CD5 down-regulation in Epstein-Barr virus associated-HLH, which represented a valuable tool for its diagnosis. However, this unusual phenotype of CD8⁺ T cells has not been investigated fully in patients with FHL2. We performed immunophenotypic analysis of peripheral blood and measured serum pro-inflammatory cytokines in five patients with FHL2. All patients showed significantly increased subpopulations of activated CD8⁺ T cells with down-regulation of CD5, which were negligible among normal controls. Analysis of T-cell receptor Vβ repertoire suggested the reactive and oligoclonal expansion of these cells. The proportion of the subset declined after successful treatment concomitant with reduction in the serum levels of cytokines in all patients except one who continued to have a high proportion of the subset and died. These findings suggest that down-regulation of CD5 on activated CD8⁺ T cells may serve as a useful marker of dysregulated T cell activation and proliferation in FHL2.