Autoimmunity Reviews 9 (2010) 488–493

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Autoimmunity Reviews

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The autoimmune lymphoproliferative syndrome: A rare disorder providing cluesabout normal tolerance☆

Joseph C. Turbyville a,⁎, V. Koneti Rao b

a Department of Allergy-Immunology, Walter Reed Army Medical Center, 6900 Georgia Avenue NW, Washington, DC 20307, USAb ALPS Unit, LCID, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA

☆ Disclaimer: The views expressed in this article arereflect the official policy of the Department of Army, DepGovernment.⁎ Corresponding author. Tel.: +1 202 782 6848; fax:

E-mail address: joseph.c.turbyville@us.army.mil (J.C

1568-9972/$ – see front matter. Published by Elsevierdoi:10.1016/j.autrev.2010.02.007

a b s t r a c t

a r t i c l e i n f o

Available online 17 February 2010

Keywords:ALPSAutoimmune cytopeniaDouble negative T cellsEndotheliumFas

The autoimmune lymphoproliferative syndrome (ALPS) is characterized by chronic, non-malignantlymphoproliferation, autoimmunity often manifesting as multilineage cytopenias, and an increased risk oflymphoma. While considered a rare disease, there are currently over 250 patients with ALPS being followedat the National Institutes of Health in Bethesda, Maryland. Most of these patients have a mutation in the genefor the TNF receptor-family member Fas (CD 95, Apo-1), and about one-third have an unknown defect ormutations affecting function of other signaling proteins involved in the apoptotic pathway. While ALPS is oneof the few autoimmune diseases with a known genetic defect, there remain unanswered questions regardinghow a defect in apoptosis results in the observed phenotype. In addition to shedding light on thepathophysiology of this rare and fascinating condition, studying ALPS may improve our understanding ofnormal tolerance and more common, sporadic autoimmune disorders.

those of the author and do notartment of Defense, or the U.S.

+1 202 782 7093.. Turbyville).

B.V.

Published by Elsevier B.V.

Contents

1. Background and epidemiology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4882. Clinical presentation and natural history . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4893. Diagnosis and treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4894. Why autoimmune cytopenias? The role of the endothelium in autoimmunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4905. Parallels between immunity and tolerance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4916. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492Take-home messages. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493

1. Background and epidemiology

The autoimmune lymphoproliferative syndrome (ALPS) was firstidentified as a distinct clinical entity by Canale and Smith in 1967 and isstill occasionally referred to as Canale–Smith syndrome [1]. Nearly30 years after the first case report, the underlying defect was deter-

mined to be a failure of lymphocyte apoptosis, with long-livedlymphocytes proliferating and their accumulation causing lymphade-nopathy, splenomegaly, and autoimmune cytopenias. In 1992 a geneticmutation in the “death receptor”, Fas (TNFRSF6), was discovered in amouse model exhibiting lymphoproliferation associated with circulat-ing TCR αβ+ DNT cells (CD3+,CD4−/CD8− double negative Tlymphocytes) [2]. Shortly thereafter mutations in the same moleculewere shown tounderlie the humandisease, since noted to beALPS [3,4].Mutations in similar molecules involved in apoptosis (Fas-L, CASP10,CASP8, andNRAS) have been shown to underlie a handful of ALPS cases,and a recent study found somatic mutations in Fas among patientspreviously labeled with an unknown genetic defect [5]. There arecurrently over 400 cases of ALPS reportedworldwide fromvarious racial

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and ethnic backgrounds. The prevalence is unknown, but it is thoughtto often go undiagnosed due to variable phenotypic expression anda constellation of symptoms that overlap many other hematologicconditions [6].

2. Clinical presentation and natural history

The most common presenting symptoms of ALPS are persistentlymphadenopathy, splenomegaly, and recurrent autoimmune cytope-nias. The lymphadenopathy can be modest or massive, but typicallypersists for years regardless of the extent [7]. In addition to peripheraladenopathy, patients will often have enlargement of abdominal andthoracic lymph nodes appreciated on CT scan or ultrasound [8]. Ifbiopsied, lymph nodes typically show marked paracortical hyperplasiathat needs to be distinguished from malignant lymphoma. Interfolli-cular areas are expanded and populated by TCR αβ+ DNT cells [9].

The first clinical manifestation of ALPS is often chronic lymphade-nopathyand/or splenomegaly in anotherwisehealthychild. Themedianage of onset of these symptoms is typically about 24 months, but somechildren have presented earlier in infancy with pallor and bruisingassociated with hemolytic anemia and thrombocytopenia [10]. Clinicalmanifestations are typically most severe in early childhood, parallelingthe age of expansion of the lymphocyte repertoire in children, and tendto improve in adolescents and adults.

The degree of splenomegaly is variable, but nearly always presentin the absence of splenectomy. In addition to posing a risk of traumaticsplenic rupture, splenomegaly can contribute to cytopenias throughsequestration. Hepatomegaly is often observed, however, liverdysfunction due to autoimmune hepatitis or hepatitis C is relativelyuncommon, but has complicated the course of some ALPS patientsreceiving multiple blood transfusions [11].

The most common autoimmune conditions seen in ALPS arehemolytic anemia, thrombocytopenia, and neutropenia but otherautoimmune conditions have been reported including Guillian–Barresyndrome, glomerulonephritis, uveitis, and liver disease [10]. Multipleautoantibodies have been demonstrated, even in the absence of overtautoimmune disease [12].

In addition to autoimmunity, patients with ALPS carry an increasedrisk of developing hematologic malignancy. The gene encoding Fas hasbeen proposed to act as a tumor suppressor since it is silenced in manytumors, thus underscoring the importance of apoptosis in tumorsurveillance [13]. The risk of an ALPS patient developing Hodgkin'slymphoma is estimated at 50 times that of the general population andthe risk of non-Hodgkin's lymphoma is increased 14 fold [14,15]. TheALPS associated lymphoma cohort studied at the NIH Clinical Centerwhere currently 259 individuals with ALPS, belonging to 164 familiesare enrolled, consists of seventeen patients (12 males and 5 females)from13 families. Their median age at lymphoma diagnosis was 17 years(range 6.9 years to 60 years). Nine patients had Hodgkin's lymphoma(HL), 8 patients had B cell non-Hodgkin's lymphoma (NHL). Fifteen outof 17 patients had germline heterozygous mutations of the Fas geneaffecting the intracellular portion of the protein, one patient had agermline mutation in the NRAS gene and one patient had no mutationdetected in the Fas or NRAS genes. Four patients, 3 with HL, and 1 withNHL are deceased due to progressive disease. This underscores theimportance of surveillance for lymphoma in ALPS in families with apertinent clinical history. ALPS should also be suspected as a possiblediagnosis in patients with a history of previous lymphoma presentingwith non-malignant lymphadenopathy and increased DNT cells inperipheral blood and/or lymph nodes during follow up.

Autosomal dominant transmission of heterozygous germlinemutations account for the majority of ALPS cases, but homozygousmutations with a severe disease phenotype have been described [16].The fact that Fas exists as a trimer on the cell surface helps explainwhy this heterozygous condition results in dominant expression. Theodds of assembling a functional Fas trimer with one gene affected are

1 in 8. Nonetheless, pedigrees of families carrying an ALPS mutationreveal some family members who carry the genetic defect but havemild or absent phenotypic expression of the disease [17]. Thissuggests that other factors may be involved in determining pheno-typic expression; a notion supported by a recent study which founddisproportionate expression of HLA B44 among patients with a mildphenotypic expression of ALPS [18].

3. Diagnosis and treatment

The diagnostic criteria for ALPS include non-malignant lymphade-nopathy and/or splenomegaly persisting for longer than 6 months,defective Fas mediated lymphocyte apoptosis as assayed in vitro, andelevated circulating TCRαβ+DNT cells. Supporting features include afamily history of ALPS, typical histopathology on lymph node orspleen biopsy, and genetic mutations in any of the genes encoding Fasor other related apoptosis signaling proteins [6].

Laboratory findings in ALPS include lymphocytosis with a Th2cytokine profile as well as elevated IL-10 and vitamin B12. Patientsalso display hypergammaglobulinemia with multiple circulatingautoantibodies. Anemia is nearly universal owing to a combinationof factors including hypersplenism, autoimmunity, and iron deficien-cy. Eosinophilia andmonocytosis are also frequent findings in patientswith ALPS, although the mechanism for these is uncertain [19,20]. In astudy of 187 ALPS patients and family members, a sub-group withpersistent eosinophilia was identified and found to have higherperipheral blood leukocytes of multiple lineages and a highermortality rate than among ALPS patients without eosinophilia [21].Interestingly, FAS mediated eosinophil apoptosis, the eosinophiliccytokine profiles and response to IL-5, and anti-eosinophil antibodiesall appeared normal; leaving unanswered the question of theunderlying mechanism for eosinophilia in these patients.

If ALPS is suspected based on clinical findings, specializedlaboratory evaluation includes flow cytometry for peripheral bloodcirculating TCR αβ+ DNT cells and the lymphocyte apoptosis assay.The precise function of TCR αβ+ DNT cells is uncertain, but thesesignature cells of ALPS have other surface markers suggesting theywere previously CD8+ senescent T cells [22]. A regulatory role issuggested by their presence in post-allogeneic bone marrowtransplant patients [23]. The lymphocyte apoptosis assay is performedwith lymphocytes cultured with IL-2 and stimulated with phytohe-magglutinin. A monoclonal antibody directed against Fas is thenadded and normal control lymphocytes undergo considerable celldeath whereas those from ALPS patients are relatively spared.

Once diagnosed, ALPS is categorized as type I, II, III, or IV dependingon the location of the genetic mutation. Types Ia and Ib refer tomutations in the genes encoding Fas or Fas-L respectively. In 2004,type Imwas proposed to describe patients with a somatic mutation inFas. Types IIa and IIb refer to mutations in Caspase 10 and Caspase 8,and type III refers to those whomeet clinical criteria for ALPS but haveno identifiable genetic defect. Among patients followed at the NIH,about 70% are type Ia, b5% have been classified as Ib, IIa, or IIb, and theremainder fall into the “unknown” (type III) category. Type IV ALPSinvolves mutations in the NRAS oncogene, a member of the p21 RASsubfamily of small GTPases [24]. Patients with an activating mutationof NRAS have diminished activity of the proapoptotic protein BIM,which is critical in the non-receptor mediated mitochondrialapoptosis pathway. Discovery of the ALPS phenotype with mutationsof NRAS showed that this condition can result from defects in eitherthe extrinsic (receptormediated) or intrinsic (mitochondrial) apoptosispathways.

A recent study proposed using circulating IL-10 and Fas-L levels inaddition to TCR αβ+ DNT cells to reliably diagnose ALPS [25].Circulating IL-10 levels have been shown to be consistently elevatedin ALPS patients and a reliable marker for disease expression [26]. Thecombination of the 3 markers (DNT cells, IL-10, and Fas-L levels in

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blood) was found useful in diagnosing ALPS, and possibly superior tothe lymphocyte apoptosis assay since the assay might miss patientswith somatic Fas mutations, in which the majority of circulating cellsdo not have the Fas mutation.

Clinical management of ALPS patients includes surveillance forlymphoma in addition to symptomatic management of ALPS relatedcytopenias with immunosuppressive medications [27,28]. Lymphnode enlargement should be followed regularly, and should includethose not palpable on physical exam. Periodic CT scan of the chest,abdomen, and pelvis can be helpful in evaluating and monitoringlymphadenopathy, and positron emission tomography (PET) scanninghas been shown to be useful in discriminating benign frommalignantlymphadenopathy [29]. Historical clues such as fever, night sweats,fatigue, loss of appetite, and weight loss should also be elicited to helpdistinguish lymphoma from fluctuations of benign ALPS associatedlymphadenopathy.

Splenomegaly should be monitored and patients at the NIH receive afiberglass spleenguard toprotect against splenic rupture.Abouthalf of theALPS patients followed at the NIH clinical center have had a splenectomy,and some have succumbed to fatal pneumococcal bacteremia. Based onthis experience, lifelong antibiotic prophylaxis and periodic pneumococ-cal immunization is recommended for all asplenic ALPS patients.

Management of immune as well as splenic sequestration relatedcytopenias in ALPS patients is similar to that used in other patientpopulations. Fig. 1 is a treatment algorithm based on the experience atthe NIH. Oral corticosteroids and other steroid sparing measuresincluding mycophenolate mofetil are usually considered first line, withsplenectomybeing a last resort only in severe refractory cases. Rituximab

Fig. 1. Management suggestions for ALPS a

is also reserved for the most severe cases since a retrospective study ofALPS patients receiving rituximab found the toxicity outweighed thebenefit in most [30].

4. Why autoimmune cytopenias? The role of the endotheliumin autoimmunity

The fact that the vast majority of autoimmunity in ALPS is directedagainst circulating hematopoietic cells and their ubiquitous intravascu-lar proteins is significant and suggests that either: 1) Fas mediatedapoptosis, in addition to eliminating redundant lymphocytes, may beparticularly important for maintaining tolerance to antigens ubiquitousin the bloodstream, or 2) the endotheliumacts as the first line of defenseagainst development of autoimmunity. A few lines of evidence suggestthat the latter is the case, and that the cytopenias seen in ALPS arethe combined result of a defect in apoptosis and a normal functioningendothelial barrier that shields extravascular antigens from circulatingautoreactive lymphocytes. In other words, the endothelium is to auto-immunity what physical barriers such as the skin, gut, and respiratorymucosa are to the immune response.

Innate immunity has become an intense area of research in recentyears, mostly focused on understanding pattern recognition receptorsand antimicrobial peptides. Sometimes taken for granted are the truefirst line of defense against non-self antigens: the physical barriersformed by the skin, gut, and lungs.When these become compromised,as is the case in burn patients, the host quickly becomes susceptible toopportunistic pathogens. The endothelium probably acts in a similarmanner with regards to inappropriate responses to self. Lymphocytes

ssociated chronic refractory cytopenia.

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typically do not migrate out of the vascular space without specificcytokine and chemokine signals directing them. In the case of ALPS,patients have evidence of proliferation of autoreactive lymphocytes,but they primarily suffer due to cytopenias from autoimmunityagainst antigens found within the vascular space.

Clues to the pathophysiology of a condition can often be found inconsidering other disease states in which it occurs. Autoimmunecytopenias have been described in T cell disorders including Digeorgesyndrome and HIV [31,32], as well as B cell disorders such as commonvariable immunodeficiency and chronic lymphocytic leukemia [33,34].In fact, cytopenias are themost commonmanifestation of autoimmunityin all primary immunodeficiencies [35], and have also been reported inother systemic autoimmune conditions [36]. Autoimmune cytopeniasare found in post-transplant states of both solid organ and stem cells, aswell as in chronic infections includingHelicobacter pylori, hepatitis C, andtuberculosis [37–39]. Is there a common pathophysiologic mechanismleading to development of autoimmune cytopenias in these conditions?It would appear as though dysregulation of multiple immune mechan-isms (T cells, B cells, and complement) could all lead to autoimmunecytopenias.

The common pathophysiologic mechanism may not be what leadsto cytopenia, but rather what is protecting against development ofother autoimmune conditions. Perhaps in a host who is susceptible toautoimmunity due to primary or secondary immune defects, theendothelial barrier protects the individual from further organ-specificautoimmune disease. However, the intravascular antigens remainexposed to the dysregulated immune cells, thus explaining the highincidence of cytopenias in ALPS and other conditions of altered im-mune function.

Viewing the endothelium as the first line of defense against auto-immunity might explain how an infection, immunization, or anyinflammatory condition could trigger an autoimmune response.Inflammatory cytokines can cause non-specific migration of lympho-cytes across the endothelium and into the target tissue. If the patienthappens to have circulating autoreactive lymphocytes directed againstthat target tissue, there is a greater chance of a successful and inappro-

Fig. 2. Unified model of im

priate immune response to self. Likewise, this concept also helps explainhow a patient might have circulating autoantibodies in the absence ofovert autoimmunity. Migration and contact with the target tissuemightbe a prerequisite for development of high affinity antibodies and apathogenic immune response.

5. Parallels between immunity and tolerance

Drawing parallels between the role of barriers in autoimmunity andthe immune response begs the question ofwhether other parallels existbetween the mechanisms for tolerance and those for immunesurveillance. Autoimmune disease is often characterized in terms ofdefects in central versus peripheral tolerance,much in the sameway theimmune response is often divided into innate and adaptive mechan-isms. An alternative approach would be a more unified view of theimmune system; one that depicts immunity and tolerance as comple-mentary functions of a single system directed toward a common goal.

This unified view might approach the immune system as a processcomposed of sequential levels of defense that is responsible fordefending against invaderswhile simultaneouslymaintaining toleranceto self. Fig. 2 represents a simple version of such a process; showing howeach level of defense contributes to achievementof the commongoals ofthe immune response and tolerance. Using this approach, the apparentparadoxical association of immunodeficiency with autoimmunity doesnot seem like a paradox at all.

By envisioning the immune system in this manner, each immuno-deficiency and autoimmune disease could be categorized by the level(or levels) at which the system is breached. The same breach in defensethat diminishes the body's ability to defend against a dangerous antigenmight increase the likelihoodof an inappropriate response to self antigens.

An early complement deficiency would be an example of a breachat the first level: predisposing to both infections with pyogenicorganisms as well as autoimmunity in the form of systemic lupus. Atthe second level, immunity can be compromised either by a defect inantigen receptors, such as occurs in toll-like receptor defects, or by achange in the antigen, such as occurs when certain viruses are able

munity and tolerance.

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to evade an immune response through mutation of their surfaceproteins. Likewise, a breakdown in antigen recognition is thefundamental problem in molecular mimicry, which is implicated innumerous autoimmune diseases. A breach of the third level leads toimmunodeficiency in the bare lymphocyte syndrome, in which loss ofMHC II leads to inability tomount an effective immune response. Whilethe exactmechanisms have not beenworked out for each disease, it hasbecome obvious that for multiple autoimmune conditions, possessing acertain HLA type is a critical genetic determinant of risk for diseasedevelopment.

ALPS would most appropriately be characterized under the putativefourth level since the defect results in a failure of a fundamentallymphocyte response: Fas receptor mediated apoptosis. Breach of thisfourth level can also encompass multiple immunodeficiency statesincludingdefects of both T cell and B cell antigen receptors and signalingpathways such as severe combined immunodeficiency, NEMO andIRAK-4 deficiency, X-linked agammaglobulinemia, and common vari-able immunodeficiency. In addition to predisposition to various types ofinfections, many of these conditions also carry an increased risk ofautoimmunity.

Given the complexity and efficiency of the immune system, breachof a single level might not be sufficient to result in autoimmunity inmost patients. In the case of immune mediated cytopenias, forexample, molecular mimicry has been implicated in multiple chronicinfectious states [32,39,40]. A patient with ALPS who also possesses acertain HLA type and develops a chronic infection associated withmolecular mimicry might be at high risk to develop autoimmunity,whereas the riskmight be abrogated if any one of these three factors isnot present.

In addition to “Immunity” and “Tolerance”, a third column could beadded to this schema labeled “Tumor Surveillance”. This is the othercritical function of the immune system, and one that is often adverselyaffected in patients with immunodeficiency and autoimmunity whoalso have a propensity to develop lymphoreticular malignancies. ALPSrepresents a classic example of immune dysregulation in which allthree elements are affected, although the immunodeficiencywould beconsidered mild relative to most other conditions involving immunedysregulation (Fig. 2).

6. Conclusions

The autoimmune lymphoproliferative syndrome results from adefect in Fas mediated lymphocyte apoptosis. Autoimmunity in ALPS isprimarily directed against intravascular antigens; a phenomenon thatlikely underscores the role of the endothelium in normal tolerance.Consideration of the endothelium as a first line of defense againstautoimmunity is a novel theory supported bymultiple lines of evidence.As inmanyother autoimmuneconditions, ALPS patients are predisposedto autoimmune cytopenias and malignancy; a phenomenon possiblyexplained by the unified view of the immune system. By studying raredisorders like ALPS, particularly thosewith awell defined genetic defect,we should gain a better understanding of the pathological processesunderlying more common autoimmune conditions.

Take-home messages

• ALPS should be considered in the differential diagnosis of any patientwith persistent lymphadenopathy and/or splenomegaly associatedwith recurrent autoimmune cytopenias.

• Appropriate screening and confirmatory laboratory evaluation canhelp establish a diagnosis of ALPS.

• The endothelium likely acts as a barrier to autoimmunity in the sameway the skin, gut, and lungs provide barriers to infection.

• Viewing the immune system as a series of barriers, or levels of defense,underscores thesimilaritiesbetween immunityandtoleranceandmighthelp explain the co-existence of immunodeficiency and autoimmunity.

Acknowledgement

This research was supported by the Intramural Research Programof the NIH, NIAID, Bethesda, MD 20892.

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B lymphocyte stimulator expression in pediatric systemic lupus erythem

Hong SD, et al. (Arthritis Rheum 2009;60:3400–3409.) assessed the expsystemic lupus erythematosus (SLE) or juvenile idiopathic arthritis (JIA). Bpatients with JIA (n=54) at the beginning and end of a 6-month interimmunosorbent assay and for blood leukocyte full-length BLyS and Dpolymerase chain reaction (normalized to 18S expression). Healthy siblingBLyS protein andblood leukocyteBLySmRNA levelswere each significantlymRNA levels,were correlatedwith disease activity. In contrast, plasmaBLylevels being elevated to degrees similar to those in pediatric SLE. Among JIAIn both pediatric SLE and JIA, the BLyS expression profiles remained stableadult SLE, plasma BLyS protein and blood leukocyte BLySmRNA levels arewith disease activity points to BLyS as a candidate therapeutic target in pedarthritis, plasma BLyS protein levels are normal in JIA despite elevated bloeither of the BLyS parameters and disease activity in JIA calls for circumspdisorder.

Study of functional variants of the BANK1 gene in rheumatoid arthriti

BANK1 gene variants have previously been identified as systemic lupus etested whether they are associated with rheumatoid arthritis (RA) a(rs17266594) and two potentially functional (rs10516487 and rs3733197enrolled four different cohorts: 1,080 RA patients and 1,368 healthy coSweden, 288 RA patients and 287 healthy controls from Argentina, and 2genotyped for BANK1 single-nucleotide polymorphisms (SNPs) using a Tallele and genotype distributions was performed with the chi-square trs10516487 and rs17266594 BANK1 polymorphisms. However, there wrs3733197, therewas an increase in themajor allele among patients in evin the Spanish (P=0.01, odds ratio [OR] 1.17 [95% confidence interval (91.72]) populations. They found a significant association of rs10516487 (P1.17 [95% CI 1.07–1.29]) with RA in the pooled analysis. In a 3-SNP hsignificantly associatedwith RA (P= 0.005, OR 1.14 [95% CI 1.04–1.25]).against RA (P=0.0004, OR 0.82 [95% CI 0.74–0.92]). Such results suggestwith a low risk.

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atosus and juvenile idiopathic arthritis patients

ression of B lymphocyte stimulator (BLyS) in patients with pediatriclood samples collected from patients with pediatric SLE (n=56) andval were analyzed for plasma BLyS protein levels by enzyme-linkedeltaBLyS messenger RNA (mRNA) levels by quantitative real-times (n=34) of these patients served as controls. In pediatric SLE, plasmaelevated, andplasmaBLySprotein levels, but not blood leukocyte BLySS protein levelswere normal in JIA despite blood leukocyte BLySmRNApatients, neither BLyS parameterwas correlatedwith disease activity.at 6months. The authors' findings indicate that, as previously noted inelevated in pediatric SLE. The correlation of plasma BLyS protein levelsiatric SLE. Contrary to previous observations in adultswith rheumatoidod leukocyte BLyS mRNA levels. The absence of correlation betweenection prior to assigning BLyS as a candidate therapeutic target in this

s

rythematosus (SLE) susceptibility markers; however it has not beens well. In a recent study intended to investigate one functional) gene variants,Orozco G, et al. (Arthritis Rheum2009;60:372–379)ntrols from Spain, 278 RA patients and 568 healthy controls from88 RA patients and 288 healthy controls fromMexico. Samples wereaqMan 5'-allele discrimination assay. Statistical analysis comparingest. They did not find a significant association between RA and theas an increase in the major alleles among RA patients. Similarly, forery cohort. Nevertheless, this skewing reached statistical significance5% CI) 1.03–1.32]) and Argentinean (P=0.04, OR 1.31 [95% CI 1.00–=0.005, OR 1.15 [95% CI 1.04–1.28]) and rs3733197 (P=0.0009, ORaplotype analysis, they found that the major TGG haplotype wasIn addition, they found a common CAA haplotype that was protectivethat BANK1 SNPs and haplotypes may contribute to RA susceptibility