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B cell immunodeficiency
Sara Mohammad Abuel Gassim November 2009
Introduction
• B lymphocytes, named after their site of origin in the bursa of Fabricius in birds or in
the bone marrow in humans, form the basis for humoral immunity by their
production of immunoglobulins.
• B-cell disorders are divided into defects of B-cell development/ immunoglobulin
production (immunodeficiencies) and excessive/uncontrolled proliferation
(lymphomas, leukemias).
Immuodeficiency• Immunodeficiency is the failure of the immune system to protect against disease or
malignancy.
• Primary Immunodeficiency is caused by genetic or developmental defects in the
immune system. These defects are present at birth but may show up later on in life.
• Secondary or acquired immunodeficiency is the loss of immune function as a result
of exposure to disease agents, environmental factors, immunosuppression, or aging.
• Bacterial, viral, protozoan, helminthic and fungal infections may lead to B cell, T
cell, PMN and macrophage deficiencies.
• Most prominent among these is acquired immunodeficiency syndrome (AIDS).
• Secondary immunodeficiencies are also seen in malignancies.
Pathophysiology• During fetal development, hematopoiesis including lymphopoiesis, is multicentric.
• After birth, the bone marrow becomes the exclusive production site for lymphoid
progenitors.
• B and T cells, type 2 dendritic cells, and natural killer (NK) cells share a common
ancestor, ie, common lymphoid progenitor (CLP).
• CLP differentiates into 2 intermediate progenitors: early B cells and
T/NK/dendritic trilineage cells. Both continue their development in the bone
marrow through an antigen-independent process called primary lymphopoiesis
(PL).
• Recognized stages of PL are pro-B cell, pre-B cell, immature B cell, and mature B
cell.
B cell development
• Secondary B lymphopoiesis is an antigen-dependent process and occurs in the
germinal center of peripheral lymphoid organs with specific antibody production.
• Secondary T lymphopoiesis is also an antigen-dependent process and occurs in the
thymus.
• Secondary lymphopoiesis (SL) begins when mature B cells enter the extrafollicular
area of lymphoid tissue and differentiate into short-lived plasma cells and memory
cells after first being stimulated by antigen-presenting cells.
• Memory cells travel to the primary follicle, where, after exposure to dendritic
cells, they differentiate into centroblasts (immunoglobulin class-switch).
• Centroblasts progress to centrocytes with high-affinity antibody production, and
then they differentiate further to long-term memory cells and plasmablasts. The
latter migrate back to the bone marrow and start producing immunoglobulins.
• The earlier the defect, the more devastating the effect on lymphopoiesis.
• Defects occurring at the CLP stage or those affecting processes common to B-
and T-cell development result in combined immunodeficiency involving B, T,
and NK cells.
Primary immunodeficiency
• Primary B-cell disorders result in a complete or partial absence of one or more
immunoglobulin isotypes.
• Regardless of the primary cause, the symptoms depend on the type and severity of
the immunoglobulin deficiency and the association of cell-mediated
immunodeficiency.
• In general, severe immunoglobulin deficiency results in recurrent infections with
specific microorganisms in certain anatomical sites.
IgG deficiency
• IgG deficiencies may be divided into 2 categories. The first is selective IgG
deficiency, which consists of an isolated deficiency of IgG with normal levels
of IgA, IgM, IgD, and IgE. The second is a deficiency of IgG accompanied by
inadequate levels of other immunoglobulin isotypes.
• This may occur in various conditions, including X-linked
agammaglobulinemia (X-LA), common variable immunodeficiency (CVID),
and hyper-IgM syndromes.
X-linked agammaglobulinemia(XLA)
• Also known as Bruton agammaglobulinemia, is the result of a mutation of the
BTK gene. Pro-B cells are present in normal number, but they are unable to
mature to pre-B cells.
• The BTK gene is present on Xq21.3-q22, and its defect results in deficiency of
Bruton tyrosine kinase.
• Non-XLA is the result of mu heavy-chain gene deficiency that leads to abortive
production of IgM and failure of B-cell development.
• Activated tyrosine kinases generate a second wave of messengers by activating
serine/threonine kinases or phosphatases pathways.
• Three major pathways have been identified: the inositol phospholipid
hydrolysis pathway, the phosphatidyl inositol-3-kinase pathway, and the Ras
pathway.
• These pathways converge toward the activation of transcription factors,
resulting in B-cell activation and proliferation.
Bruton’s Tyrosine Kinase• Signalling molecule B-cell development into anti-body producing plasma cells.• 5 domains all of which can be affected by disease causing alterations.
XLA – summary
• Btk gene mutation.
• Loss of functional tyrosine kinase.
• Blocked B cell maturation.
Common Variable Immunodeficiency(CVID)
• Mature B cells are normal in number and morphology but fail to differentiate to
plasma cells because of defective interaction between T and B cells, mostly
caused by a T-cell defect. This defect is thought to be related to a decreased
number and/or function of CD4+ T lymphocytes or, occasionally, to an increased
number of CD8+ T lymphocytes.
• Abnormal responses of B cells to many usual stimuli have also been identified in
vitro.
• The underlying abnormality in selective IgM deficiency is a defect of helper T-
cell and excessive suppressor T-cell activity.
• The disorder is characterized by a low level of IgM. IgG levels are normal, but
the IgG response is usually decreased.
• Helper T-lymphocyte deficiency has been incriminated in the pathogenesis of
transient hypogammaglobulinemia of infancy (THI) and immunodeficiency with
thymoma.
• The primary defect in selective IgA deficiency is related to a failure of B cells to
differentiate to mature isotype-switched surface IgA-positive B cells and IgA-
secreting plasma cells with appropriate stimuli. The basis for the defect is not
known.
• B cells in IgA deficiency activated via CD40 and interleukin-10 are capable of
synthesizing and secreting IgA. Defective helper T-cell and excessive suppressor T-
cell activities are occasionally present.
• Cytokine abnormalities have also been described.
• IgG2 is the most common of IgG subclass deficiencies. It occurs either alone or with
IgG4 or IgA deficiency. Its hallmark is an inability to generate antibodies to
polysaccharides.
Hyper-IgM immunodeficiency
• Individuals with this type of immunodeficiency have low IgA and IgG concentrations
with abnormally high levels of IgM.
• These patients cannot make a switch from IgM to other classes which is attributed to
a defect in CD40L on their CD4 cells. They are very susceptible to pyogenic
infection and should be treated with intravenous gamma-globulins.
Thymoma
• Some patients with thymomas have an associated IgG deficiency. In most cases, the
thymoma is composed of a benign type of spindle cell, and both B- and T-cell
deficiency have been reported.
• Panhypogammaglobulinemia and deficient cell-mediated immunity usually occur.
• This condition is usually referred to as Good syndrome.
• Removal of the thymoma does not reverse the immunoglobulin deficiency, and
patients may benefit from IgG replacement therapy to prevent recurrent infection.
Transient hypogammaglobulinemia
• Children, at birth, have IgG levels comparable to that of the mother.
• Because the half life of IgG is about 30 days, its level gradually declines, but by
three months of age normal infants begin to synthesize their own IgG.
• In some infants, IgG synthesis may not begin until they are 2 to 3 years old. This
delay has been attributed to poor T cell help.
• This results in a transient deficiency of IgG which can be treated with gamma-
globulin.
IgA deficieny
• This is the most common antibody deficiency and results in chronic infections at
mucosal surfaces since IgA is the secretory antibody which protects these surfaces.
• Since IgG and IgM can compensate, to a significant degree, for the lack of IgA, this
deficiency often goes unnoticed since it usually does not cause serious problems.
• A few patients with IgA deficiency may also develop additional antibody deficiencies
(for example deficiencies in IgG) and/or autoimmune disease with time.
X-linked immunodeficiency with hyper-IgM(XHM)
• Is related to a deficiency in gp39 (CD40 ligand).
• B cells can initiate the immune response by producing IgM, but they are not
capable of operating the class-switching, hence the overproduction of IgM and
the decrease or absence of the other immunoglobulin isotypes.
• Liver disease, sclerosing cholangitis, and liver/GI malignancies are common in
these patients.
• The expression of CD40L on the surface of biliary epithelial cells has suggested a
role for CD40-CD40L interaction in the pathogenesis of these complications
through defective control of intracellular pathogens such as Cryptosporidium
parvum, which has been recognized as an important pathogen in these patients.
Secondary immunodeficiency
• Also known as acquired immunodeficiency.
• one is born with normal immune responses but some secondary factor or
occurrence causes a decrease in immune responses.
• Secondary immunodeficiency is induced by factors such as:
Malnutrition• Most common cause of secondary immune deficiency
• Protein-Calorie malnutrition can lead to abnormalities of T cells, B cells and
phagocytes.
• Atrophic and fibrotic thymus.
• Reduced lymphocyte proliferation in response to antigens.
Malignancy• Immunodeficiency caused by lymphoid tumours e.g. leukaemia, lymphoma,
plasma cell dyscrasias
• Hodgkin’s lymphoma: causes classic example of T-cell deficiency.
• Chronic lymphocytic leukaemia: causes classic example of B-cell deficiency.
Lymphocyte Depletion Hodgkin's Lymphoma
Human Immunodeficiency Virus (HIV)• Human retrovirus
• RNA genome.
• Targets host cell immune
system itself…
“abnormalities in
every arm of the
immune system”
Other causes for secondary immunodeficiency:
• Irradiation - exposure to X-rays and gamma rays. Causes a decreased production of lymphocyte precursors in the bone marrow.
• Cytotoxic drugs such as many used in cancer chemotherapy. Causes a decreased production of lymphocyte precursors in the bone marrow.
• Corticosteroids – anti-inflammatory steroids. Damages lymphocytes.
• Aging. Adaptive immunity, especially cell-mediated immunity, tends to deminish
with aging. • Removal of the spleen. Decreased ability to remove microbes that enter the blood.
Category Examples
Endocrine Diabetes mellitus.
GI Hepatic insufficiency, hepatitis, intestinal lymphangiectasia, protein-losing enteropathy.
Hematologic Aplastic anemia, cancer, graft-vs-host disease, sickle cell disease.
Iatrogenic Certain drugs: chemotherapeutic drugs, immunosuppressants, corticosteroids Immunodeficiency Disorders: Some Drugs That Cause Immunosuppression radiation therapy; splenectomy.
infectious Cytomegalovirus, Epstein-Barr virus, HIV, measles virus, varicella-zoster virus.
Nutritional Alcoholism, undernutrition.
Physiologic Physiologic immunodeficiency in infants due to immaturity of immune system, pregnancy.
Renal Nephrotic syndrome, renal insufficiency, uremia.
Rheumatologic RA, SLE
Other Burns, chromosomal abnormalities (eg, Down syndrome), congenital asplenia, critical and chronic illness, histiocytosis, sarcoidosis.
Other clinical conditions• In studies performed to improve the accuracy of early diagnosis of retinoblastomas,
markedly reduced blood and lacrimal fluid IgG levels have been found in persons
with stage III-IV retinoblastoma.
• A relationship between febrile convulsion and IgG subclass deficiencies has also
been demonstrated. One study found that IgG subclass deficiencies may be
responsible for an increased incidence of febrile infections, which result in a higher
incidence of seizures in children who are predisposed to febrile seizures.
• IgG2, IgG4, and IgA subclass deficiencies may play a role in the pathogenesis of
allergic colitis in children.
• Infants with a definitive diagnosis of noninfective colitis displayed a high
prevalence of IgA, IgG2, and IgG4 deficiencies.
• Although some reports have suggested a strong relationship between IgG
subclass patterns and atopic disorders, other studies have not found this
association.
T cell deficiencies with variable degrees of B cell deficiency
Ataxia-telangiectasia
• Ataxia-telangiectasia is a deficiency of T cells associated with a lack of
coordination of movement (ataxis) and dilation of small blood vessels of the facial
area (telangiectasis).
• T-cells and their functions are reduced to various degrees.
• B cell numbers and IgM concentrations are normal to low. IgG is often reduced
and IgA is considerably reduced (in 70% of the cases).
• There is a high incidence of malignancy, particularly leukemias.
• The defects arise from a breakage in chromosome 14 at the site of TCR and Ig
heavy chain genes.
Wiskott-Aldrich syndrome (WAS)
• This syndrome is associated with normal T cell numbers with reduced functions,
which get progressively worse. IgM concentrations are reduced but IgG levels are
normal.
• Both IgA and IgE levels are elevated. Boys with this syndrome develop severe
eczema, petechia (due to platelet defect and thrombocytopenia).
• They respond poorly to polysaccharide antigens and are prone to pyogenic
infection.
• Wiskott-Aldrich syndrome is an X-linked disorder due to defect in a cytoskeletal
glycoprotein, CD43.
Combined Immunodeficiency
Deficiencies in Cell Mediated Immunity
SCID
• SCID refers to severe combined immune deficiency which results in no, or low
numbers of, functional B and T cells. By far the most profound effect on the
immune response is the lack of T cells.
• Children with SCID are usually diagnosed in their first six months of life because
of severe bacterial, viral and fungal infections. They must be kept isolated from
any potential for infection.
• This is the classic “baby in the bubble” syndrome.
• The prognosis is very poor unless their immune system can be reconstituted by
providing normal bone marrow stem cells through transplantation from an HLA-
matched donor.
• Since the development of B cells and T cells depends on a number of critical
steps, all going according to plan, a defect in any of these critical steps will result
in SCID.
• A defect in the RAG genes which are required for gene rearrangement of both the
T cell receptor and antibody will result in an inability of either T cells or B cells
to reach maturity.
• A common genetic defect leading to SCID is a problem in the gene coding for the
gamma chain of the IL-2 receptor. This chain is also part of the receptors for IL-
4, IL-7, IL-9 and IL-15. A defect in the gamma chain knocks out the activity of
all of these important cytokines and renders the immune response completely
ineffective.
• A defect in the JAK kinase signal transduction pathway activated by these
cytokines has a similar effect.
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