( )* CVID) (Common variable immunodeficiency. IgM (Immunoglobulin A) IgA (Immunoglobulin G) $ $%&' $%&' ()* +

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2 CVID B B B +(7<% $% '" '" B +(7<% k< EB / ); " l." B +(7<% k< / B +(7<%! +W@! H E "' Q/2- BAFFR ); / / )/ /[- +<^ / 9 EB F / Y BAFFR ); Pf H! ^ Y %/ #5! J"( f I/ $9 $fl )/ / (Transitonal B cells). +/ % 0 )! 5 10) CVID 8 / 15 +(2 )%/, < + H '" #L (7%! 19/13 (7% 26 % 0 15) P% Y 15 )fsg +(/# )/ +." f 5D )9 + European Society for Immunodeficiencies) 3/ / +(/#." Y- q / CVID * $fl (ESID. 1 7"L r5 #5 / Y s9! '" /?( O% +"/ )9 %% 10 /" " / C3 B )! El"^ / " Y- "( / +('- Y 5D )9 +K(, +(7<% +!%"L + +-! 'S% / (Peripheral blood mononuclear cell PBMC).$Y- /l Q/! 5D )9 +K(, +(7<% +!%"L $fl )9 + M/G " ]" 'S% 7BY +/ +!%"L +/ /: (Phosphate-buffered saline) PBS '" rl/ l / / 1800 $W% l 20 M" E 7BY.! C3.(" Q9 " ;S% 2) " ;S% +N, M/G +K(, +(7<% +N ;S% $33, $ /l 7BY %83 I! O/ "S% / (PBMC C?%." +/:L E /F E% /%3 * PBS! < 1 )3 / "" *K PBS 7<D.": / )K?%% M/G " YT '-): Anti--PE (Exbio) FITC "- YT <% )K?%% B 100 PerCP (." ' /l,/ `D / l 20 M" ( )3 / " ' *K PBS Y /, )%B! C3 Anti-CD19- (Exbio) +(+:! B 5 Anti-CD38- (Exbio) '- (B&D) +%<Y '0% +<% (.! 'S% +/: 2:."" 2: B23 +'"B* % / "( +('- +K + Mann-Whitney )!:." Y- q / +/ # U5% ) W P < 0/050 ".@ '/ MN89,%83= MN89!- S3S +: U5% ) 3 E."( UT / CVID )/ / $! % )V KS '0% /B +($SW /V )/ *.(2) " 3 $*! " +(PKB A ID, +'" " +(); /.$% '" 9 +'" 7#Y (Inducible T-cell costimulator ICOS) EW +'"[3 CD19 (TACI) CAML +'" ( H *Z B-cell activating factor receptor) B 7<% +'" %/.(3) $% '" Q/2- CD21 7#Y CD20 CD81 (BAFFR 2;3 + +""L ; % )/! "G/ 10 / A "^ ; 7^ ]'" CVID " / / `Y ; +(.$% '" %.(4) " akd CVID EW O (( '"d3 +" Y c B +(7<% EB $Y*3!B EW +'"[3 +'9.$% MS ; MNeD Tumor necrosis factor receptor superfamily) / +'" ( +(7<%!33: )" 7#Y / W Pf H (TNFRSF BLyS ) BAFF $( 9 M#5."/ PK% " g ( '" 2 ztnf4 THANK TALL-1 +(7<% ($% `% < /F BAFF."' `D BAFF )2Y. U T +(7<%,/" +'" U +(7<%! h8 iw +'" ( H *Z B 7<% +'".(5) IgG +'" +'" B +(7<% $* U +(7<% IgM 7#Y +'"- % BAFF 7#Y EW +'"[3 (TACI) CAML -. Ee (BCMA) 7<% k< );: 2 (BAFF-R) H BAFF +'"- " Ee BAFF '"- % ( V +'" 9 +'"- f / c B 7<% + + +Pf.(5) $% / El c B +(7<% A U5% " / / 2 R +/[- +(7<% 1 R (Transitional) +/F ]/ +! $( 7DF / c B +(7<% " + B +(7<% E )"Y BAFFR BAFF "ly +(Q / k< )" ml +^ +(7<%.(6) '" +^ B +(7<% /NBY +/[- +(7<% E" / + H BAFF +'"[3 1 R +/[- +<^ / B 7<% CD19 +(0* 9 k< F / c B +/[- / ; #5 L." (! / CD ! /357 /

3 CVID B B.1 L/C/!./)BK59) /!(Intravenous / IV) ( H(!!5B )1 /!M5( A'35(5B55/ )'B5 18'4C 3 N(Subcutaneous) SC )'B51 8'3C )R9@ Q O5P 23410(./,-+!) 2 >?@) (Immunoglobulin G) IgG :; / >?@ 89! ('( A A'2' )/1 SD IgA! (Immunoglobulin M) IgM A'35(5B55/ (Immunoglobulin A) A69! ( E'0F D/! A'.'C5B!/-*,- '(! ) 5B / 6.C.'35(5BB5J/( HI)* AGB.9 O5P -( TP./ '( )* S3 )* 2 / B +(7<% / )/ EB*. 9 )2 )/ /." ;:,D! C3 (): AB G9 B; +( E B +'F9 +(7<% E%%83.(7) " H( (): ID, +('"- / IgAD " +(+/ R * * h% Bruton CVID (Immunoglobulin A deficiency) +('-! %/ '! /G /." +(/# 2^ CVID <L! (+/ f * / 2 B 7<% B +(7<% ('-! +<L!." $( high <% u Y " (/[-) Transitional Y #5 / /q "." * CD38 high.$y- /l %/ / +%<Y Q/! 'S% (7<% (Dot plot) +5 /, ' (! " v / (Forward scatter FSC) <L '" 3 / h% $#L C?% " Y- (Side scatter SSC) vl '" 3 h% / (R1) "- Gate %S.(1 EB) " Y- Gate (FL1) FITC FSC )9 / B Transitional B +(7<% `% "G/." %D / "( "G/ 0 +('- 5D $K (10/43± 3/36) "( '- / 5D )9 B +(7<% $ +/ # MS (2/85± 1/50) / ' - B +(7<% `% "G/ /G /.(P< 0/001) / '- $K (1/00± 0/38) "( '- / Transitional.(2 EB) (P< 0/260) $" +/ # MS (1/13 ± 0/45) ( FSC) " # $!%& '! (A.1 ( SSC) )' # $!%& ' (Forward scatter,-.( /" 0 (B.$ Gate *+ # (Side scatter.r1 Gate 1 # B +($%S B +($%S Y %/ #5 J"( Y w/ 8 )/ 5D )9 +/[-! )0( +W@ %/. P% / %/ (+: % U5% H( $% (+/@ ( ($SW! H2Y (K ($SW +: 6% ! /357 / 33

4 CVID B B CD38 CD19 C CD38 D CD19 $6 B Transitional B " 55" "4- (.3-.2 / '- / B +(7<% `% "G/ (C "( '- / B Transitional +(7<% `% "G/ (B "( '- / B +(7<% `% "G/ (A / '- / B Transitional +(7<% `% "G/ (D CVID )/! "G/ 10 /./ /l #F U5%! +3 K ry /.(8) $% SG ^ P B +(7<% "# )* 2 T^ +#5 / +%<Y! EG^ w (' "G/ "( '- K / CVID )/ /!."/ /l +3 U5% / +/ # /F B +($%S )* / B +(7<% "G/ H2Y CVID )/! 9 YF '( 9 7< <3 +($%S zs " (.(9) $% B +(7<% 2 k< / $KB CVID +/ <G! +/ +." +: +'" " +(7<% CD19 ICOS TACI El! ; " V,; yd, c B +(7<% EB.$% '" Q/2- BAFFR CD81 )!.$% MS ; MNeD '" O (( +'"d3 " Y B +(7<% 2 k< " Y / f H BAFFR ); (); +'"D / CVID )/ * / B +(7<% E." +! "# 1394! /357 /

5 CVID B B / HfL $% BAFFR ); +/! / E9 +(); l (Transitional) /[- +<^ / B +(7<% k< ); $fl f *3. " c B 7<% " %. %/ 2 BAFFR ); HfL +/ f $9 u Y,; MN89 B; E `/."* f +/ 2;3! / I/ <W"D "/ % / +'/ +)3 EG^.<W '0* / *({3 4F +'/ '!K^ +/ rd +L / +Y!.$% )fsg B23. +/20%?% " +(! r<5 "# '".@ M#5 h% d(." ( )* H( CVID Y / B 7<% +(W@! /2, (Subpopulations) %S +($#L! +#5 "# 0 (.$% )9 +( +/ * / H3! L +'"D! s/9 %S." +/ +'" ( )* $% B - /l Pf +($#L! r<5 '" # +" F + +'" 2Y /F 2 %S +($#L! m< f-:h3 +('-! CVID 8 )/.- /l 'S% / B +(7<%! +W@! #5 / /q ( B +(7<% "G/." Y- /l %/ / /[- B +(7<%. MS $ H( "( Y $K / Y / /[-! B,; yd! " S- /F)( YF!. / # References 1. Yong PF, Thaventhiran JE, Grimbacher B. "A rose is a rose is a rose," but CVID is Not CVID common variable immune deficiency (CVID), what do we know in 2011? Adv Immunol 2011; 111: Mouillot G, Carmagnat M, Gerard L, Garnier JL, Fieschi C, Vince N, et al. B-cell and T-cell phenotypes in CVID patients correlate with the clinical phenotype of the disease. J Clin Immunol 2010; 30(5): Park MA, Li JT, Hagan JB, Maddox DE, Abraham RS. Common variable immunodeficiency: a new look at an old disease. Lancet 2008; 372(9637): Bacchelli C, Buckridge S, Thrasher AJ, Gaspar HB. Translational mini-review series on immunodeficiency: molecular defects in common variable immunodeficiency. Clin Exp Immunol 2007; 149(3): Losi CG, Silini A, Fiorini C, Soresina A, Meini A, Ferrari S, et al. Mutational analysis of human BAFF receptor TNFRSF13C (BAFF-R) in patients with common variable immunodeficiency. J Clin Immunol 2005; 25(5): Sims GP, Ettinger R, Shirota Y, Yarboro CH, Illei GG, Lipsky PE. Identification and characterization of circulating human transitional B cells. Blood 2005; 105(11): Kopecky O, Lukesova S. Genetic defects in common variable immunodeficiency. Int J Immunogenet 2007; 34(4): Piqueras B, Lavenu-Bombled C, Galicier L, Bergeron-van der Cruyssen F, Mouthon L, Chevret S, et al. Common variable immunodeficiency patient classification based on impaired B cell memory differentiation correlates with clinical aspects. J Clin Immunol 2003; 23(5): Schatorje EJ, Gemen EF, Driessen GJ, Leuvenink J, van Hout RW, van der Burg M, et al. Age-matched reference values for B-lymphocyte subpopulations and CVID classifications in children. Scand J Immunol 2011; 74(5): ! /357 / 33

6 Journal of Isfahan Medical School Received: Vol. 33, No. 357, 1 st Week, January 2016 Accepted: Investigating the Frequency of the Peripheral Blood B and Transitional B Cells in the Patients with Common Variable Immunodeficiency Abstract Mohammad Alihassanzadeh 1, Nahid Eskandari PhD 2, Mazdak Ganjalikhani-Hakemi PhD 3, Roya Sherkat MD 4 Original Article Background: Common variable immunodeficiency (CVID) is a heterogeneous set of immunological abnormalities including decreased serum levels of antibodies (hypogammaglobolinemia), at least for two isotopes of immunoglobulin, and impaired antibody response to infection or vaccination. Thus, it is associated with increased susceptibility to infections. This study aimed to investigate the frequency of B cells in the patients with CVID in Isfahan city, Iran. Methods: Blood samples were collected from the patients with substitutive immunoglobulin (Ig) therapy before immunoglobulin infusion. Then, peripheral blood mononuclear cells (PBMC) were isolated via Ficoll-Hypaque density centrifugation. Flow cytometry method was employed to determine the frequency and phenotype of the B and transitional B cells using the antibodies of CD19-FITC (Exebio), -PE (Exebio), and CD38 PE (BD Exebio). Findings: There was significant difference in the proportion of the peripheral blood B cells in the patients with CVID, compared to the healthy subjects (P < 0.001). But, there was insignificant difference in the proportion of the transitional B cells in the patients, compared to the healthy subjects (P = 0.267). Conclusion: The results show that there is insignificant difference in the proportion of the transitional B cells in the patients with CVID, compared to control group. However, more studies should be carried out concerning mutation in the involved genes to understand more aspects of this disease. Keywords: Plasma cell, BAFF-R, B Transitional, Peripheral blood mononuclear cells (PBMC) Citation: Alihassanzadeh M, Eskandari N, Ganjalikhani-Hakemi M, Sherkat R. Investigating the Frequency of the Peripheral Blood B and Transitional B Cells in the Patients with Common Variable Immunodeficiency. J Isfahan Med Sch 2016; 33(357): MSc Student, Department of Immunology, School of Medicine AND Student Research Committee, Isfahan University of Medical Sciences, Isfahan, Iran 2- Assistant Professor, Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran 3- Assistant Professor, Cellular and Molecular Immunology Research Center AND Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran 4- Associate Professor, Acquired Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran Corresponding Author: Nahid Eskandari PhD, neskandari@med.mui.ac.ir 1394! /357 /