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

1. IMMUNOLOGIC
DEFICIENCY SYNDROMES

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.

22. THANK YOU