This document summarizes several primary immunodeficiency disorders including:
- X-Linked Agammaglobulinemia of Bruton, caused by mutations in BTK leading to absent or low antibodies and recurrent infections. Treatment is immunoglobulin replacement.
- Common Variable Immunodeficiency, a heterogeneous group characterized by low all antibody classes. Causes recurrent infections.
- Isolated IgA Deficiency results in low mucosal immunity and infections of respiratory and gastrointestinal tracts.
- Hyper-IgM Syndrome prevents isotype switching beyond IgM production due to defects in CD40/CD40L, leading to low IgG and susceptibility to pneumonia.
It also briefly discusses Secondary immun
2. Divided into:
Primary immunodeficiency disorders:
are almost always genetically determined.
Secondary immunodeficiency states:
may arise as complications of :- infections; malnutrition;
aging; or side effects of immunosuppression, irradiation,
or chemotherapy.
3. primary immunodeficiency disorders:
X-Linked Agammaglobulinemia of Bruton:
characterized by failure of B-cell precursors
( pro-B cells and pre-B cells) to mature into B cells.
is due to mutations in a cytoplasmic tyrosine
kinase, called B-cell tyrosine kinase (Btk).
The BTK gene is found on long arm of X chromosome
( Xq21.22).
As X-linked disease, this disorder is seen almost entirely
in males.
4. The disease become apparent about age of 6 months.
there is recurrent bacterial infections of respiratory
tract.
Because antibodies are important for neutralizing
viruses as well, these patients are also susceptible
to certain viral infections.
For similar reasons, Giardia lamblia, an intestinal
protozoon , that is normally resisted by secreted
IgA, causes persistent infections in these patients.
5. The classic form of this disease has the following
characteristics :
o B cells are absent or markedly decreased in circulation.
o serum levels of all classes of immunoglobulins are
depressed.
o Germinal centers of lymph nodes, Peyer
patches, appendix, and tonsils are underdeveloped or
rudimentary.
o Plasma cells are absent throughout the body.
o T cell-mediated reactions are entirely normal.
The treatment of X-linked agammaglobulinemia
is replacement therapy with immunoglobulins.
6. Common Variable Immunodeficiency :
Heterogeneous group of disorders.
The feature common to all patients is
hypogammaglobulinemia affecting all antibody classes
but sometimes only IgG.
The diagnosis is based on exclusion of other causes
of decreased antibody production.
As expected in a heterogeneous group of
disorders, both sporadic and inherited forms of disease
occur.
In inherited forms, there is no single pattern of
inheritance.
7. In contrast to X-linked agammaglobulinemia
, most patients have normal numbers of mature B
cells in blood and lymphoid tissues.
These B cells, however, are not able to differentiate
into plasma cells, so plasma cells are absent.
There are defects in ability of T cells (TH2 ) to send
activation signals to B cells.
According to others, some patients have intrinsic
B-cell defects , as well as abnormalities of
T cell-mediated regulation of B cells.
8. The clinical manifestations are caused by antibody
deficiency, and hence resemble those of X-linked
agammaglobulinemia.
affects both sexes equally, and the onset of symptoms
is later in childhood or adolescence.
Histologically the B-cell areas of lymphoid tissues
(lymphoid follicles in nodes, spleen, and gut) are
hyperplastic.
9. Isolated IgA Deficiency:
extremely low levels of both serum and secretory IgA.
It may be familial ( Inherited ); or acquired in
association with toxoplasmosis, measles, or other
viral infections.
Because IgA is major immunoglobulin in external
secretions, mucosal defenses are weakened, and
infections occur in respiratory, gastrointestinal, and
urogenital tracts.
10. The basic defect is in differentiation of naive
(un stimulated ) B lymphocytes to IgA-producing cells.
Although the molecular basis of this defect is still
unknown, intrinsic B cell defects or altered T cell help
(TH2 ) have been implicated.
In most patients the number of IgA-positive B cells
is normal, but only a few of these cells can be
differentiated into IgA plasma cells .
Serum antibodies to IgA are found in 40% of patients.
11. Hyper-IgM Syndrome :
T cell disorder in which functionally abnormal T cells
( TH2 ) fail to induce B cells to make antibodies of
isotypes other than IgM .
When Naive (unstimulated) B cells stimulated by
antigens, IgM and IgD antibodies are produced
first, this is followed by sequential formation of
IgG, IgA, and IgE antibodies.
This normal immune response is called isotype
switching.
The ability of IgM producing B cells to turn on depends
on interaction between CD40 molecules on B cells and
CD40L expressed on T cells.
12. In approximately 70% of cases, the mutations
affect the gene for CD40L, which maps to Xq26.
These patients have X-linked form of disease.
In the remaining patients, the mutations affect
CD40 , or an enzyme called activation-induced
deaminase which is required for isotype
switching .
The disease in these latter groups of patients is
inherited in autosomal recessive pattern.
13. Clinically, patients present with recurrent
pyogenic infections because the level of IgG
is low.
They are also susceptible to pneumonia caused
by intracellular organism Pneumocystis
carinii, because of defect in cell-mediated
immunity.
The serum contains normal or elevated levels
of IgM, but no IgA or IgE , and extremely low
levels of IgG.
The number of B and T cells is normal.
14. DiGeorge Syndrome (Thymic Hypoplasia) :
Results from failure of development of third
and fourth pharyngeal pouches that give rise to
thymus , parathyroids , and portions of face
and aortic arch.
Thus, these patients have a variable loss of
T cell-mediated immunity (owing to hypoplasia
or lack of thymus) ; tetany (owing to lack of
parathyroids) ; and congenital defects of heart
and great vessels.
15. Absence of cell-mediated immunity is reflected
in poor defense against certain viral
, fungal, and protozoal infections.
Patients are also susceptible to intracellular
bacteria.
Immunoglobulin levels may be normal or
reduced, depending on severity of T-cell
deficiency.
In 90% of cases of DiGeorge Syndrome there is
deletion affecting chromosome 22q 11.
16. Severe Combined Immunodeficiency Diseases:
Defects in both humoral and cell-mediated immune
responses.
Patients with SCID are extremely susceptible to
recurrent, severe infections by a wide range of
pathogens, including Candida albicans, P.
carinii, Pseudomonas, cytomegalovirus, and bacteria.
Without bone marrow transplantation, death occurs
within the first year of life.
The most common form( 50% to 60% of cases) is
X-linked, and hence SCID is more common in boys
than in girls.
17. The remaining cases of SCID are inherited as
autosomal recessives with deficiency of enzyme
adenosine deaminase (ADA).
These Mutations prevent development of
CD4+ T cells.
CD4+ T cells are involved in cellular immunity and
provide help to B cells, and hence results in combined
immunodeficiency.
18. Immunodeficiency with Thrombocytopenia and Eczema
(Wiskott-Aldrich Syndrome):
It is X-linked recessive disease ( Xp11.23 ) ,
characterized by thrombocytopenia, eczema, and
recurrent infections, ending in early death.
The thymus is morphologically normal, but there is
progressive secondary depletion of T lymphocytes in
peripheral blood and in T-cell zones (paracortical areas)
of lymph nodes, with variable loss of cellular immunity.
The only treatment is bone marrow transplantation.
19. Genetic Deficiencies of Complement System:
complement system play a critical role in both
inflammatory and immunologic responses.
Hereditary deficiencies described for all
components of complement system and for
inhibitors.
Hereditary deficiency of C3 :
result in increased susceptibility to infection
with pyogenic bacteria.
20. Inherited deficiencies of C1, C2 ,and C4 :
increase the risk of immune complex- mediated
diseases ( e.g, SLE ), possibly by impairing
the clearance of Ag-Ab complexes from
the circulation.
Lack of C1 esterase inhibitor:
allow C1 esterase activation with generation of
vasoactive mediators that result in hereditory
angioedema.
21. Deficiencies of ( C5 to C9 ) :
The terminal components of complement
[ C5, 6, 7, 8, and 9 ] are required for
membrane attack complex , which involved
in lysis of organisms ,result in recurrent
neisserial ( gonococcal and meningococcal )
infections.