1. Cовременная концепция
диагностики и терапии
агаммаглобулинемии с
дефицитом В клетокГ
Гусева М.Н.
IV Всероссийская Школа по Клинической иммунологии
Пушкинские Горы,Псковская область 27 янв-2февр 2013
Гусева М.Н., IV Всероссийская школа по клинической иммунологии, 2013г.
2. PEDIATRICS
Official Journal of the American Academy of
Pediatrics
Vol 127 №5 may 2011
Clinical Features That Identify Children With
Primary Immunodeficiency Diseases
Гусева М.Н., IV Всероссийская школа по клинической иммунологии, 2013г.
3. Proportion of Children With the 10 Warning Signs Grouped According to PID Type
No Defianble PID
(N=133), n(%)
Definable PID
(N = 430), n(%)
B Lymhocyte
(N = 92), n(%)
Positive family history 6(4) 148(34)а 24(26)а
≥2 deep-seated infections 15(11) 44(10) 8(9)
≥2 episodes of pneumonia 34(26) 105(24) 34(37)
Abscesses(deep skin or
organ)
9(7) 56(13) 2(2)
Multiple acute otitis media 47(35) 64(15)а 29(31)
≥2 sinus infections 21(16) 23(5)а 14(15)
Persistent thrush 5(4) 63(15)а 2(2)
Intravenous antibiotics 56(42) 241(56)а 41(45)
≥2 mo of oral antibiotics
with little effect
3(2) 75(17)а 14(15)
Failure to thrive 7(3) 135(31)а 9(10)
Гусева М.Н., IV Всероссийская школа по клинической иммунологии, 2013г.
6. AGAMMAGLOBULINEMIA
By Col. Ogden C. Bruton, M.C., U.S.A.
Washinton, D.C.
The complete absence of gamma globulin in human serum with a normal total
protein asdet determined by electrophoretic analysis does not appear to have as yet
been reported in the literature. Stern1 mentions two cases of hypoproteinemia in
children who had “almost complete absence of gamma globulin and were
singularly free of infection.” Schick2 reported a similar congenital case without
nephrosis with a review of the literature in wich the total protein was low, the
gamma globulin fraction low, and edema present. The latter findings in
nephrosis are well known. Krebs3 reported a case in wich there was a
“depression of gammaglobulin in hypoproteinemia due to malnutrition.”
The present author had the opportunity of following a patient without nephrotic
syndrome, with normal nutrition, with complete absence of the gamma globulin
fraction and normal total serum protein through several years of many
infections including 19 episodes of clinical sepsis in wich some type
pneumococcus was recovered by blood culture 10 time. This entity, wich, it
was found, could be controlled by supplying gamma globulin as contained in
concentrated immune human serum globulin, appears to be unique.
Pediatrics, 9, 722-728, 1952
Гусева М.Н., IV Всероссийская школа по клинической иммунологии, 2013г.
7. Mancini G, Carbonara AO, Heremans JF.
Immunochemical quantitation of antigens by single
radial immunodiffusion.
Immunochemistry. 1965 Sep;2(3):235-54.
Гусева М.Н., IV Всероссийская школа по клинической иммунологии, 2013г.
8. Agammaglobulinemia
Immunological profile:
- Absent/low immunoglobulin serum levels
- Absence of circulating B cells (CD19+:<1%)
CD19
CD3
Healthy subject Agammaglobulinemic patients
Гусева М.Н., IV Всероссийская школа по клинической иммунологии, 2013г.
9. Controllo Agamma
CD34
CD19
Cytofluorimetric analysis of bone marrow’s B cells
CD34+CD19+
CD34-CD19+
CD34+CD19+
CD34-CD19+
Healthy controls Agammaglobulinemic patients
Гусева М.Н., IV Всероссийская школа по клинической иммунологии, 2013г.
10. pro-B cell
Myc, NFAT, NF-
kB, AP-1
pre-B cell
Btk
Гусева М.Н., IV Всероссийская школа по клинической иммунологии, 2013г.
11. • Ген состоит из 19
экзонов
• Локализован на
Xq21.3-Xq22
• 90% всех случаев
агаммаглобулинемии
XLA
• 10% аутосомно-
рецессивное
наследование
Гусева М.Н., IV Всероссийская школа по клинической иммунологии, 2013г.
13. X-Linked Agammaglobulinemia
Definitive(Диагноз достоверен)
Male patient with less than 2% CD19+ B cells and at least one of the following:
1) Mutation in Btk
2) Absent Btk mRNA on northern blot analysis of neutrophils or monocytes
3) Absent Btk protein in monocytes or platelets
4) Maternal cousins, uncles or nephews with less than 2% CD19+ B cells
www.esid.org
Гусева М.Н., IV Всероссийская школа по клинической иммунологии, 2013г.
14. Probable(вероятен)
Male patient with less than 2% CD19+ B cells in whom all of the following are positive:
1) Onset of recurrent bacterial infections in the first 5 years of life
2) Serum IgG, IgM and IgA more than 2SD below normal for age
3) Absent isohemagglutinins and /or poor response to vaccines
4) Other causes of hypogammaglobulinemia have been excluded (see Table)
www.esid.org
Гусева М.Н., IV Всероссийская школа по клинической иммунологии, 2013г.
15. Possible(предположителен)
Male patient with less than 2% CD19+ B cells in whom other causes of
hypogammaglobulinemia have been excluded (see Table) and at least one of
the following is positive:
1) Onset of recurrent bacterial infections in the first 5 years of life
2) Serum IgG, IgM and IgA more than 2 SD below normal for age
3) Absent isohemagglutinins
www.esid.org
Гусева М.Н., IV Всероссийская школа по клинической иммунологии, 2013г.
16. All other causes of hypogammaglobulinemia listed in Table 1:
1) Mu heavy chain deficiency (дефицит тяжелых цепей)
2) Lambda 5 deficiency
3) IgA deficiency
www.esid.org
Гусева М.Н., IV Всероссийская школа по клинической иммунологии, 2013г.
17. Гусева М.Н., IV Всероссийская школа по клинической иммунологии, 2013г.
18. Гусева М.Н., IV Всероссийская школа по клинической иммунологии, 2013г.
19. Гусева М.Н., IV Всероссийская школа по клинической иммунологии, 2013г.
20. Гусева М.Н., IV Всероссийская школа по клинической иммунологии, 2013г.
21. Age ofAge of
establishingestablishing
diagnosisdiagnosis
66 yearsyears 33 yearsyears 88 monthsmonths 33 yearsyears 99 monthsmonths 11 yearyear 44 monthsmonths
Clinical aspects Purulent conjunctivitis,
chronic maxillarychronic maxillary
sinusitissinusitis,, chronicchronic
pneumoniapneumonia,,
bronchiectatic disease,,
left lung resectionleft lung resection,, nosenose
bleedingbleeding
((disaggregativedisaggregative
trombocytopathya)trombocytopathya)
Recurrent otitisRecurrent otitis,,
streptodermiastreptodermia,,
rheumatoid arthritis,,
purulent
conjunctivitis,, nosenose
bleedingbleeding
((disaggregativedisaggregative
trombocytopathyatrombocytopathya
))
BilateralBilateral
pneumoniapneumonia,,
recurrent otitis,recurrent otitis,
neutropenianeutropenia,,
delay of physicaldelay of physical
developmentdevelopment,,
chronic colitischronic colitis
Purulent
conjunctivitis,,
enterovirusenterovirus
meningocephalitismeningocephalitis,,
bacterialbacterial
endocarditisendocarditis
Serum IgSerum Ig
BB --cellscells
IgGIgG --0.10.1гг//лл
IgAIgA-- 0.170.17гг//лл
IgMIgM 0.270.27гг//лл
ССD21D21 2%2%
IgGIgG --0.110.11гг//лл
IgAIgA --0.180.18гг//лл
IgMIgM 0.0060.006гг//лл
ССD19D19 0%0%
IgGIgG 2.02.0 гг//лл
IgAIgA 0.130.13 гг//лл
IgMIgM 0,010,01
ССD19D19 2%2%
Dramatic decreaseDramatic decrease
Molecular geneticMolecular genetic
researchresearch
It wasnIt wasn’’t madet made a c.881 C>Ta c.881 C>T
missense mutationmissense mutation
in exon 10 of thein exon 10 of the
BTK geneBTK gene
It wasnIt wasn’’t madet made Mother and childMother and child
have Mutationhave Mutation
Nt61delTNt61delT
Therapy nowTherapy now Regular replacement therapy with intravenous IgRegular replacement therapy with intravenous Ig
Antibacterial therapy in case of infectionAntibacterial therapy in case of infection
SymptomaticSymptomatic therapytherapy
AgeAge 2929yearsyears 1212yearsyears 1717yearsyears 1010yearsyears
Гусева М.Н., IV Всероссийская школа по клинической иммунологии, 2013г.
22. Принципы терапии
•Регулярная заместительная терапия
внутривенными иммуноглобулинами
•Лечение и профилактика
инфекционных осложнений(Антибиотики
широкого спектра действия по
индивидуальным схемам)
•Лечение аутоиммунных проявлений
•Симптоматическая терапия
Гусева М.Н., IV Всероссийская школа по клинической иммунологии, 2013г.
23. The importance of regular immune globulin replacement in patients with
antibody
deficiencies was initially attributed to its ability to provide specific antibodies
that could not be produced by these patients — in particular, antibodies to
encapsulated
organisms such as Streptococcus pneumoniae or Haemophilus influenzae.
Гусева М.Н., IV Всероссийская школа по клинической иммунологии, 2013г.
24. Контактная информация:
Гусева Марина Николаевна
педиатр, аллерголог - иммунолог, врач высшей
категории КДЦ Санкт-Петербургской Государственной
Педиатрической медицинской академии
(www.gpma.ru),член ESID, член Steering Committee of The J
Project
Контактная информация: 194100 СПб., ул. Александра
Матросова д.22
тел. для записи: 8 (812) 295 41 75
раб. телефон: 8 (812) 295 10 72
E-mail: gusevamarina@mail.ru
ФБУН НИИ эпидемиологии и микробиологии им.
Пастера, 8(812)233-48-11
Гусева М.Н., IV Всероссийская школа по клинической иммунологии, 2013г.
25. Благодарю за внимание и
сотрудничество
Гусева М.Н., IV Всероссийская школа по клинической иммунологии, 2013г.
