X-LINKED AGAMMAGLOBULINEMIA

8ruIcn': Di:ec:e
X-Linked Agammaglobulinemia
%0 basic d010ct in X-Link0d AgammagIobuIin0mia is a
1aiIur0 o1 B-Iympocyt0 pr0cursors to matur0 into B-
Iympocyt0s and uItimat0Iy pIasma c0IIs. Sinc0 t0y Iack
t0 c0IIs tat ar0 r0sponsibI0 1or producing
immunogIobuIins.
Bruton's aggamaglobulinemia or X-linked aggammaglobulinemia (XLA) is
present at birth (congenital) and is characterized by low or completely
absent levels of immunoglobulins in the bloodstream. mmunoglobulins are
protein molecules in blood serum that function like antibodies. Without
them, the body lacks a fully functioning immune system. Persons with XLA
are vulnerable to repeated, potentially fatal bacterial infections.
XLA is caused by a defect in the gene that codes for Btk. This defect leads
to blocked maturation of B cells, the cells that produce immunoglobulins.
Because other portions of the immune system is functional, people with
XLA can fight off some types of infection, such as fungal and most viral
DefiniIicn cf Ierm:
B lymphocyte - a lymphocyte derived Irom bone marrow that provides humoral immunity; it
recognizes Iree antigen molecules in solution and matures into plasma cells that secrete
immunoglobulin (antibodies) that inactivate the antigens
precursor cell -a population oI cells in the bone marrow that are incapable oI selI-renewal; they are
derived Irom progenitor cells and are the Iirst cells oI a particular blood cell line that can be recognized
due to their speciIic morphologic characteristics (e.g., proerythroblast).
B-Lymphoid Precursor Cells - Lymphocyte progenitor cells that are restricted in their diIIerentiation
potential to the B lymphocyte lineage. The pro-B cell stage oI B LYMPHOCYTE development precedes
the pre-B cell stage;Cells Irom the stage oI B LYMPHOCYTE development where B CELL HEAVY
CHAIN GENE REARRANGEMENT is completed. The pre-B cell stage is preceded by the pro-B cell
stage;Cells Irom the stage oI B LYMPHOCYTE development where B-CELL GENE
REARRANGEMENT begins. The pro-B cell stage is Iollowed by the pre-B cell stage.
Btk-Bruton's agammaglobulinemia tyrosine kinase (Btk) - is a
cytoplasmic tyrosine kinase important in B-lymphocyte development,
diIIerentiation, and signaling. Btk is a member oI the Tec Iamily oI
kinases. Mutations in the Btk gene lead to X-linked
agammaglobulinemia (XLA) in humans and X-linked
immunodeIiciency (Xid) in mice.
!atopysioIogy
n Ihe cL:ence cf 8IK, 8 |ymphccyIe: cc ncI cifferenIicIe cr mcIure. WiIhcuI mcIure 8
|ymphccyIe:, cnIiLccy-prccucing p|c:mc ce||: cre c|:c cL:enI. /: c ccn:euence,
Ihe reIicu|cenccIhe|ic| cnc |ymphcic crgcn: in which Ihe:e ce||: prc|ifercIe,
cifferenIicIe, cnc cre :Icrec cre pccr|y ceve|cpec. Ihe :p|een, Ihe Icn:i|:, Ihe
ccencic:, Ihe Feyer pcIche: in Ihe inIe:Iine:, cnc Ihe peripherc| |ymph ncce: mcy c||
Le recucec in :ize cr cL:enI in incivicuc|: wiIh X-|inkec cgcmmcg|cLu|inemic {XL/).
ereciIy FcIIern cf 8ruIcn: Di:ec:e
8cne mcrrcw
F|uripcIenIic| SIem Ce||
Lymphcic SIem
Ce||
FremcIure 8 ce||
McIure 8 ce||
(cc:ent}
8|utcn': y|c:|ne
k|nc:e enzyne
(8tk}
8ruIcn: Di:ec:e
X-Linkec /gcmmcg|cLu|inemic
Mlsslng or uefecLlve 8Lk
Loss of maLernal anLlbodles
(CaLabollzed lCg)
uefecL ln x chromosome
(x?)
uecrease lvel of lg (low or
absenL serum lg)
8locked maLuraLlon of 8 cells
lncrease suscepLlblllLy
8ruton's D|sease
8lsk for lnfecLlon 8lsk for lnfecLlon
lnfuslon of
lmmunoglobulln
lnfuslon of
lmmunoglobulln
Chorlonlc vllll
sampllng
AmnlocenLesls
D|agnost|c 1ests
Nurs|ng D|agnos|s Nurs|ng D|agnos|s
Med|cat|ons Med|cat|ons
S|gns]Symptoms
D|agnos|s
athogenes|s
$tem cell transplantation
Ccmp|iccIicn:
8ruton's D|sease
ar lnfecLlon ar lnfecLlon
CLlLls Medla CLlLls Medla
Slnus lnfecLlon Slnus lnfecLlon
MenlnglLls MenlnglLls
Skln lnfecLlon Skln lnfecLlon
8ronchlLls 8ronchlLls
SepLlcemla SepLlcemla
lneffecLlve
Alrway Clearance
lneffecLlve
Alrway Clearance
8lsk for Spread
of lnfecLlon
8lsk for Spread
of lnfecLlon
AcuLe aln AcuLe aln
8lsk for lmpalred
Skln lnLegrlLy
8lsk for lmpalred
Skln lnLegrlLy
ulsLurbed Sensory
ercepLlon audlLory
ulsLurbed Sensory
ercepLlon audlLory
lmpalred Cas
change
lmpalred Cas
change
lmpalred ComforL lmpalred ComforL
ulsLurbed Sensory
ercepLlon olfacLory
ulsLurbed Sensory
ercepLlon olfacLory
neumonla neumonla
iagnostic Test
Chorionic Villi sampling a procedure obtaining a prenatal evaluation data
early in a pregnancy by withdrawing a chorionic villi sample from fetal
membranes.
Amniocentesis an obstetric procedure in which a small amount of
amniotic fluid is removed for laboratory analysis. t is usually performed
between the sixteen and twentieth weeks of gestation to aid in the
diagnosis of fatal abnormalities.
Laboratory Studies
PerIorm initial studies measuring quantitative IgG, IgM, immunoglobulin E (IgE), and immunoglobulin
A (IgA) levels. IgG levels should be measured Iirst, preIerably aIter age 6 months, when maternal levels
decline. IgG levels below 100 mg/dL are usually indicative oI X-linked agammaglobulinemia (XLA).
The detection oI IgG, IgA, IgM, and IgE levels is related to age. Typically, IgM and IgA are
undetectable. All levels are reduced in males with XLA. Age-speciIic reIerence range values are
available to compare with the patient's level.
Once antibody levels are detected as abnormally low, conIirmation is attained by using Iluorocytometric
analysis oI B-lymphocyte and T-lymphocyte markers. CD19

B-cell levels lower than 100 mg/dL are

diagnostic oI XLA. On Iluorocytometric analysis, T-cell values (CD4

and CD8

) are usually increased.

Further analysis can be made by detecting IgG responses to T-celldependent and T-cellindependent
antigens by administering immunizations, such as an unconjugated 23-valent pneumococcal vaccine (T-
cellindependent responses) or tetanus, diphtheria, and H influen:aetype b immunization (T-cell
dependent responses).
imaging Studies
Head radiographs may demonstrate an absence oI tonsils or adenoids. Further imaging studies oI the
chest can demonstrate chronic inIections or sinopulmonary disease
Pulmonary Iunction tests are central to monitoring lung disease, oI both the obstructive type and the
restrictive type. They should be checked yearly in children who can perIorm the test (typically age 5 y).
Procedures
Endoscopy and colonoscopy can be used to assess the extent and the progression oI inIlammatory bowel
disease. Bronchoscopy can be useIul in diagnosing and tracking chronic lung disease and inIections.
Histologic Findings
In patients with X-linked agammaglobulinemia (XLA), lymphoid tissues lack germinal centers, and
plasma cells are missing Irom the lamina propria oI the gut and Irom bone marrow stores. In tissue
samples taken to evaluate inIection, the most common Iinding is an intense inIlammatory response.
Treatments
InIusion oI immunoglobulin (IVIG) to ward oII inIection
The most common treatment Ior XLA is an intravenous inIusion
oI immunoglobulin (IVIg, human IgG antibodies) every 34 weeks, Ior liIe. IVIg is
a human product extracted and pooled Irom thousands oI blood donations. IVIg
does not cure XLA but increases the patient's liIespan and quality oI liIe, by
generating passive immunity, and boosting the immune system
Antibiotics to treat inIection as they occur
These agents treat common sinopulmonary inIections (eg, pneumonia,
otitis media). Drugs, such as amoxicillin and amoxicillin/clavulanate, are
typical agents used. Fluoroquinolone therapy is useIul Ior respiratory
staphylococcal inIections and Ior patients with allergies to other medications. II
the inIection is caused by .45lasma organisms, the drug
oI choice is clarithromycin. Severe inIections may require hospitalization
and IV therapy with ceItriaxone or vancomycin.
Stem cell transplantation is a choice
Ior the treatment oI Bruton disease.
Prevention
Families with a known mutated gene can be prenatally evaluated to better prepare
for the infant's care. Testing is performed via amniocentesis or chorionic villi
sampling. After birth, testing is performed on cord blood.
!ati0nt Education
Patients and their families must understand the nature of the disease and the
importance of early treatment. dentification and treatment of common infections are
necessary for a better prognosis.
Genetic counseling is recommended for the parents and female siblings of males
who are affected. Molecular characterization and carrier detection is informative in
95% of families. Prenatal diagnosis is available
Management
Supportiv0
muItidiscipIinary approac
!a0diatrics - monit0r 1or in10ctions (tr0at wit anti-viraI
ag0nts and antibiotics), autoimmun0 dis0as0s, and
maIignanci0s
G0n0tics - g0n0tic couns0IIing, pr0nataI diagnosis (wit
DXS 159 as prob0)
ID - propyIactic gammagIobuIin
IM, IV, intrat0caI
propyIactic antibiotics
avoid immunization wit att0nuat0d Iiv0 viraI vaccin0s
Bon0 Marrow %ranspIantation
ursing iagnosis
Risk for nfection
neffective Airway Clearance
mpaired Gas Exchange
Acute Pain
Risk for mpaired $kin ntegrity
Risk for $pread of nfection
isturbed $ensory Perception : auditory
isturbed $ensory Perception : olfactory
mpaired Comfort
Latest Aews about XLA
Long-lasting memory-resting and memory-effector CD4+ T cells in human X-linked
agammaglobulinemia
ConIlicting results obtained Irom animal studies suggest that B cells play a role in maintaining long-
term T-cell memory and in skewing T-cell response toward a T-helper 2 (T(H)2) phenotype. X-linked
agammaglobulinemia (XLA) is a genetic human disease characterized by the lack oI circulating B cells
due to the mutation oI Bruton tyrosine kinase. This disease thus represents a unique model Ior studying
the role oI B lymphocytes in regulating T-cell Iunctions in humans. To this aim, we analyzed hepatitis B
envelope antigen (HBenvAg)-speciIic T-cell memory in a series oI XLA patients vaccainated against
hepatitis B virus (HBV).
e Iound HBenvAg-speciIic T lymphocytes producing interIeron-gamma, interleukin-4, or both in the
peripheral blood oI XLA patients up to at least 24 months aIter completing the standard anti-HBV
immunization protocol. The HBenvAg-speciIic T-cell Irequencies and the percentage oI patients with
these responses were not signiIicantly diIIerent Irom healthy vaccinated controls. By combining cell
puriIication and enzyme-linked immunospot assay, we Iound that eIIector CD27- T cells, which
promptly produced cytokines in response to antigen (Ag), and memory-resting CD27 T cells, which
required Ag restimulation to perIorm their Iunctions, were maintained in both XLA patients and
controls Ior up to 24 months aIter the last vaccination boost.
These data strongly suggest that B cells are not an absolute requirement Ior the generation oI eIIective
T-cell memory in humans, nor do they seem to inIluence T(H)1/T(H)2 balance.
Paroli M, Accapezzato D, Francavilla V, Insalaco A, Plebani A, Balsano F, Barnaba V. l44/
Mar 15;99(6):11-7
#010703.0
Chin I: 8ruIcn /gcmmcg|cLu|incemic, eMecicine, SepI 2008
ermc:zew:ki F/, WeL:Ier /D: Frimcry hypcgcmmcg|cLu|incemic: c :urvey cf c|inicc|
mcnife:IcIicn: cnc ccmp|iccIicn:. C J Mec. 13 Jcn:8{1):31-42. |cL:IrccI]
Sku|| S, Kemp /: IrecImenI cf hypcgcmmcg|cLu|incemic wiIh inIrcvencu:
immuncg|cLu|in, 173-3. /rch Di: Chi|c. 1 Jun:74{):527-30. |cL:IrccI]
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