Congenital immunodeficiency diseases:

Bruton agammaglobulinemia:
● Males are affected
● It is an X linked disease that results due to deficiency in tyrosine kinase which is crucial
for differentiation of pre B cells into mature B cells. The problem becomes with humoral
immunity so antibodies are absent.
● The patient does not show any symptoms the first 6 months because there are maternal
antibodies.
● Any type of infection can develop like recurrent otitis media, recurrent sinusitis,
meningitis, encephalitis.
● Premature B cells have CD19 but no CD20 (only in mature B cells). These immature B
cells are abundant.
● We can not do much in these diseases and this turns out to be quite severe.
● Fathers can not transmit this to sons.
Common variable immunodeficiency:
● It is also a humoral immune deficiency.
● Mature B cells are formed but immunoglobulins are not formed.
● It is an autosomal recessive disorder. Both females and males are affected.
● The most common infection is giardia lamblia which causes diarrhea and liver
disorders.
● This is also associated with humoral deficiency.
Hyperimmunoglobulin M syndrome:
● The first immunoglobulins produced are IgM and IgD. The rest need class switching.
● APCs like macrophages have a receptor called B7 which combines with CD27 on T
helper cells. Helper T cells have CD40 receptors which is important for class switching.
The CD40 receptor binds to MHC II B cells to undergo class switching.
● In Hyperimmunoglobulin M syndrome, there is a defect in CD40 receptors which renders
class switching impossible. Immunoglobulin M level is high while the other Ig are low.
IgM is not sufficient to fight off all infections, especially parasitic and chronic infections.
● This is an autosomal recessive disorder.
● The problem is also in humoral immunity
Severe combined immunodeficiency (SCID):
● We have B and T cell deficiency.
● We have two types: Autosomal recessive and X linked.
● We have toxic substances for lymphocytes. Adenosine deaminase deficiency leads to
accumulation of deoxyadenosine which is toxic for lymphocytes.
● It causes hyperplasia of lymphoid tissue.
● Patients are not protected against any type of infection.
● For B cell activation we need helper T cells.
● The only hope for this person is bone marrow transplantation.
 ● Age of death is 2-3 years without bone marrow transplant. There is a risk of GVHD for
this transplant.
IgA deficiency:
● We have IgA (epithelial cell antibody) in the mucous membranes of the GI and
respiratory tracts. IgA is the first line of defence in the resistance against infection, via
inhibiting bacterial and viral adhesion to epithelial cells and by neutralisation of bacterial
toxins and virus, both extra- and intracellularly.
● Patients are asymptomatic in 78% of the cases. These patients have increased risk of
developing infections and allergic reactions.
● Usually we do not transfuse whole blood but if a patient has IgA deficiency and you
transfuse whole blood to them, it will lead to severe anaphylaxis. Because we have
antibodies against IgA, our immune system will attack the IgA from the transfused blood.
DiGeorge Syndrome:
● We have microdeletion in 22q. The main defect is in the 3rd and 4th pharyngeal pouches.
From these two pouches, the parathyroid gland and thymus develop.
● There is no thymus and no parathyroid gland which means there is low T cell count and
there are hypocalcemic seizures. .
○ The low calcium levels cause increased neuromuscular excitability by decreasing
the threshold needed for the activation of neurons.
● Thymus is important for T cell development: positive and negative selection.
● There is also congenital heart disorder where the aorta and pulmonary artery are
connected to each other. There is only 1 truncus and it is called truncus arteriosus. There
is also an interrupted aortic arch.
● For tests, B cells are normal but in reality, there is secondary B cell deficiency because
we need T cells to activate B cells.
● To test for hypocalcemia, we have chvostek and trousseau signs. If you lightly tap on the
cheek, it will cause contraction of the facial muscles, this is the Chvostek test. When you
are measuring the BP and inflating the balloon, the pressure causes tetanic contractions of
the digits and causes them to flex inward, this is the trousseau sign. There is no mental
retardation.
● The treatment is thymus transplant.
Catch-22:
● It is the same as DiGeorge’s syndrome except there is no mental retardation.
● Abbreviation: Catch (C: cardiac malformation A: abnormal face T: thymic hypoplasia C:
cleft palate H: hypocalcemia
● Patient present with hypertelorism (increased distance between the eye sockets),
down-slanted eyes, +/- cleft palate
Leukocyte adhesion deficiency:
● This is innate immunity deficiency. Patients have defective integrin production
● If leukocytes do not adhere to blood vessels, it leads to increased risk of infection.
 ● We can have non pus formation because we need leukocytes to form pus.
● One of the signs is failure of umbilical cord separation.
Chronic granulomatous disease:
● It is an X linked disorder that is due to NADPH oxidase deficiency which is used to make
ROS. Patients are prone to develop many infections. Patients develop recurrent
infections.
Chediak-Higashi syndrome:
● It is an autosomal recessive disorder where we have a defect in phagolysosome
interaction. We can form lysosomes and phagosomes but these two can not interact with
each other; the lysosomes can not bind to the phagosome to digest it. This leads to the
decrease in microbial killing and will result in recurrent infections. The reason is because
the structure proteins on the lysosomes are defective which means that it can not bind to
the phagosome.
● This causes partial albinism (when melanin is not formed) but we do not know why.
● Also, patients have pancytopenia where there are too few red blood cells, white blood
cells, and platelets.
● It also causes neuropathy and hypogonadism
Hereditary angioedema:

● Bradykinin was formed from high molecular weight kininogen. Bradykinin increases
pain, causes vasodilation, and increases permeability.
 ● It is an autosomal dominant disorder that is due to C1 esterase inhibitor deficiency. C1
esterase inhibitor inhibits the kallikrein-bradykinin pathway. Its deficiency means there is
increased synthesis of bradykinin. Because bradykinin increases permeability and
vasodilation, it leads to edema.
● Edema in the neck can lead to respiratory problems like tightening of the airways.
● Patients can live normally for years and then suddenly they have edema.
Deficiencies affecting the complement system:
● If for some reason, the membrane attack complex is not formed-could be due to
deficiency of C2, C4, or C1q- bacterial or viral molecules will not be perforated and that
increases the risk of infections. The dominant manifestation is an SLE-like autoimmune
disease.
● Deficiency of C3 is rare but it is associated with severe pyogenic infections as well as
immune complex mediated glomerulonephritis.
● Deficiency of C5-C9 will result in increased susceptibility to recurrent neisseria
(gonococcal and meningococcal) infections because neisseria has thin cell walls and are
susceptible to lysis by complement.
Ataxia telangiectasia:
● It is an autosomal recessive disorder where we have T cell and IgA deficiency.
● There is a deficiency in frataxin which leads to abnormal gait, ataxia. There are also
abnormally dilated blood vessels, telangiectasia.

Acquired immunodeficiency:
HIV:
● We can not cure but we can stop the proliferation of HIV.
● It is transmitted sexually, blood products like transfusion and Iv drug use,
transplacentally, breastfeeding (we have to restrict it), and through the passage through
the birth canal.
○ If you treat with anti-retroviral therapy from the beginning of pregnancy, the risk
decreases to 10%.
● Incubation period can be up to 1 year.
● It is an RNA, enveloped virus.
● The virus needs gp120 receptor to attach to the host cells. The virus needs gp 41 to
penetrate the cell. Alongside these two receptors, they need CCR5 and CXCR4
coreceptors. These coreceptors cause transformation of the receptor which leads to easy
penetration with this gp41 into the cell.
● Some people have defective coreceptors which means they can not get AIDS but can
transmit HIV.
○ CD4 cells need both CCR5 and CXCR4. If you have a defect in one of them, it
means that HIV will take much longer to penetrate into the cell. Symptoms could
appear after 10 years of infections
 ● The symptoms depend on the count of CD4 cells.
● When we are treating HIV, we are giving reverse transcriptase inhibitors, gp41 blockers,
integrin inhibitors...
● HIV has receptors for many immune cells but mainly it attacks CD4 cells
● HIV infection is present when CD4 count is less than 200.
● HIV increases the risk of Kaposki’s sarcoma.
● As doctors we have to keep T cells in normal range
Amyloidosis:
● Amyloid is an abnormal protein, it is a hyaline eosinophilic amorphous substance that is
usually a misfolded protein and stains congo red.
● We have two types: Systemic amyloidosis and Non-systemic amyloidosis
● Chronic infections cause increased acute phase reactants (inflammation markers) in the
liver for example IL6. Amyloid associated protein is synthesized in the liver which leads
to deposition of this amyloid in the tissues, this is called AA amyloid. AA amyloid is a
misfolded protein that is synthesized in the liver because of chronic inflammation and is
derived from amyloid associated proteins
● In the kidneys, it leads to glomerulonephritis and kidney dysfunction. It leads to
cardiomyopathy in the heart.
Types of amyloid:
● Systemic:
○ Primary amyloidosis is the systemic deposition of AL amyloid which is derived
from immunoglobulin light chains. It is associated with plasma cell dyscrasias
(multiple myeloma).
○ Secondary amyloidosis is the systemic deposition of AA amyloid which is
derived from serum amyloid associated proteins (SAA).
● localized amyloidosis:
○ senile cardiac amyloidosis which is non mutated serum transthyretin depositing in
the heart.
○ Familial amyloid cardiomyopathy: mutated serum transthyretin deposits in the
heart leading to restrictive cardiomyopathy.
○ Non insulin dependent diabetes mellitus (II): amylin (derived from insulin)
deposits in the islets of the pancreas.
○ In Alzheimer, it deposits in the brain and causes mental retardation in elderely
patients. This is AB amyloid which contains amyloid precursor proteins.
○ During dialysis, beta 2 microglobulin accumulates as amyloid.