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.