X linked agammaglobulinemia

X-LINKED
AGAMMAGLOBULINEMIA
Kullapornpas Benyajirapach, MD
November 30th, 2018

Scope
◦ Introduction
◦ Epidemiology
◦ Mechanism of disease: Pathogenesis
◦ Clinical manifestations
◦ Diagnosis: Laboratory findings
◦ Management
◦ Complications
◦ Prognosis

X-Linked Agammaglobulinemia
◦ Mutations in BTK gene  absence of circulating B cells with severe reduction in all serum Ig levels
◦ T cell counts and function - in normal range
◦ Discovered by Colonel Ogden Bruton in 1952
◦ X-linked agammaglobulinemia (XLA) was the ﬁrst recognized human host
defect involving the immune system
Alessandro Plebani and Vassilios Lougaris. Stiehm’s Immune Deficiencies. 2014; 329-346.
Bruton OC. Pediatrics 1952;9:722-8.

Genetics
◦ Bruton’s tyrosine kinase (BTK) - member of the Tec family of kinases that maps to X chromosome
◦ BTK - kinase acts downstream of the pre-BCR and the BCR signaling complex  essential for B cell
activation and maturation
◦ Majority of the mutations - missense, followed by nonsense mutations, while deletions represent the
minority
◦ Mutations in BTK
can be both familial
and de novo

BTK Gene
◦ Location = Xq22.1, position 22.1 in the long (q) arm of the X-chromosome

Incidence
Worldwide
◦ 1:100,000 - 1:200,000
V. Modell et al. Immunol Res. 2014 Oct;60(1):132-44.
Alessandro Plebani, Vassilios Lougaris. Stiehm’s Immune Deficiencies. 2014; 329-346.

Incidence in Thailand
P. Benjasupattanan et al. J Clin Immunol. 2009; 29:357-364.
O. Luecha et al. J Allergy Clin Immunol. 2012.

B-cell Development and Activation

B-cell Development and Activation
◦ B cell development takes place in the bone
marrow, depends on the sequential expression
of specific gene products that regulate B cell
maturation
◦ B cell maturation starting from pro-B to pre-
B to transitional B cells that exit the bone
marrow and enter periphery
◦ Pre-B cells express the pre-BCR complex that
requires BTK for the initiation of the
downstream signaling cascade

Location of Mutant Protein in B-cells
Thomas A.E. Platts-Mills. Middleton’s Allergy 8th edition. 1146-1148.

Pathogenesis
◦ Mutations in BTK  block of B cell development in bone marrow at pro-B to pre-B stage
◦ This early developmental block  less than 1-2% of lymphocytes are B cells in the periphery
◦ Immunoglobulin levels - very low for all classes
◦ Virtually no humoral response to recall antigens

Pathogenesis
◦ Btk - expressed high levels in all B lineage cells, including pre-B cells, found in cells of myeloid series
(intermittent neutropenia can occur at onset of acute infection)
◦ Absence of BTK protein in monocytes or platelets can be detected by Western blotting or flow cytometry
◦ Female carriers of XLA can be identiﬁed by the presence of either nonrandom X chromosome inactivation
in their B cells or the mutated gene
◦ No clear correlation between mutation location on coding portion osf the gene and clinical phenotype
◦ XLA - reported in association with growth hormone deﬁciency involve mutations in the ELF4
(ETSrelated transcription factor 4) gene on X chromosome
◦ With XLA, sensorineural hearing loss can be caused by deletion mutations affecting both Btk and the
TIMM8A gene on X chromosome
Thomas A.E. Platts-Mills. Middleton’s Allergy 8th edition. 1146-1148.

Clinical Manifestations
◦ Initiate at the age of 6 and 12 months, when the maternal IgGs are catabolized
◦ Hallmark - recurrent bacterial respiratory and/or gastrointestinal infections

Physical Examination
◦ Absence of lymph nodes and tonsils (tissues normally highly populated by B cells) distinct from other forms
of antibody deficiency
◦ Small or absent tonsils also be seen in patients with some CIDs and other congenital agammaglobulinemia
A. Bonilla et al. J Allergy Clin Immunol. 2015; 136(5), 1186–1205.

Bacterial Infections
◦ Mainly caused by encapsulated bacteria: Streptococcus pneumoniae, Haemophilus influenzae,
Staphylococcus aureus
◦ Most frequent type of upper respiratory tract infection: otitis media (70%), sinusitis (almost 60%)
◦ Pneumonia: Haemophilus infuenzae - most frequent, followed by Streptococcus pneumoniae and
Staphylococcus, Pneumocystis jirovecii
◦ Septicemia: Pseudomonas, followed by H. influenzae, S. pneumoniae, and S. aureus
◦ Septic arthritis: H. influenzae and S. pneumoniae before IVIG therapy, whereas after - viral cause
◦ Bacterial meningitis

◦ Recurrent bronchitis and/or pneumonia, and general infections at the mucosal surfaces, even
immunoglobulin replacement therapy appropriately administered
◦ Major causes of bronchiectasis and chronic lung disease
◦ Partially due to inability of immunoglobulin substitution to reach the mucosal surface, where it is
expected to play a crucial protective role

◦ Gastrointestinal tract infections: Giardia lamblia (its eradication frequently unsuccessful  chronic diarrhea
and malabsorption), Campylobacter jejuni, Salmonella
◦ Helicobacter species: pyoderma gangrenosum-like ulcer (Helicobacter cinaedi), skin infection (Helicobacter
bilis), refractory chronic pleurisy (Helicobacter equorum-like) and systemic infection (Flexispira
rappini,aHelicobacter-like organism)
◦ Mycoplasma species: involving the respiratory and urogenital tract, and joints
◦ Infectious pericarditis from Morganella morganii

Enteroviral Infections
◦ Susceptible to enterovirus: poliovirus, echovirus, and coxsackievirus
◦ Vaccine-associated poliomyelitis after live attenuated oral vaccine (Sabin)
◦ Progressive neurological symptoms; ataxia, paresthesias, loss of cognitive skills, and neurosensorial hearing
loss
◦ Meningoencephalitis
◦ Enteroviral CNS infections - frequent before introduction of IVIG (one of major causes of death)
◦ Enteroviral nfections may still occur even on IVIG

Enteroviral Infections
◦ High-dose IVIG treatment may be efficient in controlling enterovirus CNS infection
◦ But limited number of patients studied – non statistical conclusions
◦ Intrathecal delivery of IVIG also been used
◦ Combined treatment with IVIG and pleconaril - effective in controlling enteroviral infection
◦ High Ig levels in patients under regular IVIG - protective role against enteroviral infection (especially when
IVIG initiated at high doses before the age of 5)

Other Infections
◦ Hepatitis C infection from contaminated IVIG preparations in early 1990s
◦ Pneumocystis - rare cause of pneumonia
◦ Recurrent pyoderma
◦ Chronic gingivitis

Arthritis
◦ 20% of XLA patients
◦ Clinical indistinguishable from rheumatoid arthritis (RA)
◦ Enteroviral or Mycoplasma infection - associated with the rheumatic manifestations

Neutropenia
◦ 10-25% of patients
◦ Unknown mechanism
◦ Pseudomonas ecthyma - typically seen in neutropenic XLA patients

Other Manifestations Reported
◦ Glomerulonephritis
◦ Membranous glomerulopathy
◦ Alopecia
◦ Amyloidosis
◦ Von Recklinghausen disease.
◦ Conjunctivitis
◦ Gastric adenocarcinomas
◦ Cutaneous T cell lymphomas
◦ Gastric adenocarcinoma
◦ Deletions encompassing BTK and TIMM8A -
immunodeficiency and sensorineural hearing loss
◦ Growth hormone deficiency with
agammaglobulinemia - ELF4 gene may be
involved in pathogenesis

Laboratory Findings
◦ IgG level usually < 100 mg/dL
◦ IgM level < 20 mg/dL
◦ IgA level < 10 mg/dL
◦ Peripheral blood CD19+ B-cell counts < 2%
◦ Differential diagnosis of agammaglobulinemia: X-linked and autosomal recessive forms and some patients
with ‘‘severe’’ CVID with immunoglobulins and B cells in the agammaglobulinemic range
◦ Measurement of specific antibodies might not be necessary in patients with IgG levels in the
agammaglobulinemic range

Specific Antibody Response

AUTOSOMAL RECESSIVE
AGAMMAGLOBULINEMIA

Autosomal Recessive Agammaglobulinemia
◦ Components of the pre–B-cell immunoglobulin receptor:
◦ IgM heavy chain (IGHM),
◦ Part of the surrogate light chain (l 5/14.1, CD179B),
◦ Immunoglobulin receptor–associated signal transducing chains Ig-a and Ig-b (CD79A, and CD79B),
◦ Cytoplasmic adapter molecule B-cell linker protein (BLNK).
◦ Only one autosomal dominant monogenic agammaglobulinemia: defects of transcription factor 3 (TCF3)
◦ Translocation of a gene encoding leucine-rich repeat containing 8 (LRRC8)  highly similar form of
AAGAM

Management
◦ Antimicrobials
◦ IgG replacement
◦ Careful attention to pulmonary status

IVIG
◦ Maintaining pre-infusion IgG levels > 500 mg/dl  reduction in number of infections, reducing
hospitalizations
Dosage:
◦ IVIG 400 mg/kg per dose every 3 to 4 weeks
◦ SCIG 100 mg/kg per dose every week
◦ Long-term follow-up - many cases the trough level of 500 mg/dl (which was once considered protective) is
not fully protective
◦ Secreted antibody (IgA) - not replaceable
◦ After almost two decades of follow-up, patients regularly on IVIG may develop chronic lung disease

IVIG High Dose in Enterovirus Infection
◦ Enteroviral meningoencephalitis should be treated with high doses IVIG with measurable antibody to
the infecting virus
◦ Chronic enteroviral meningoencephalitis - usually by ECHO viruses, can cause serious morbidity or
mortality
◦ Occurs rarely, even with IgG therapy
◦ Treatment of meningoencephalitis – at least partly successful with high doses IVIG (maintaining IgG trough
levels >1000 mg/dL)
◦ Intraventricular IgG has resulted in a cure in 1 reported case

Antibiotic Prophylaxis

Complications
◦ Before introduction of appropriate therapy, patients would die before the age of 10 years from invasive
infections: sepsis and meningitis
◦ Lung complications - main cause of morbidity and mortality
◦ CLD - major cause of death
◦ Due to: inability of immunoglobulin substitution to reach the mucosal surface
◦ Respiratory physiotherapy - important supportive preventive measure

Bronchiectasis and Chronic Lung Disease

Lung Transplantation in CLD
◦ Lung transplantation should be considered for XLA patients with life-threatening chronic lung disease eg.
severe bronchiectasis
◦ Experience is too limited

Transplantation in XLA
◦ Gene therapy - complications leukemia
◦ Bone marrow transplantation - successful in the mouse model but not in humans

O. Luecha et al. J Allergy Clin Immunol. 2012.

X linked agammaglobulinemia

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