IMMUNOL

LECTURE 12: IMMUNODEFICIENCY DISORDERS

Ourlad Alzeus G. Tantengco, MD, PhD| 3rd TERM | A.Y. 2022-2023
August 4, 2023

IMMUNODEFICIENCY
● Autoimmunity – system attacks host cells and tissues
● Immunodeficiency – system fails to protect
○ Primary immunodeficiency
■ Genetic or developmental defect
■ Caused by defects in virtually any
gene involved in immune
development or function, innate or
adaptive, humoral, or cell mediated,
plus genes not previously
associated with immunity
○ Secondary immunodeficiency
■ Acquired immunodeficiency
■ Loss of immune function that results
from exposure to an external agent,
often an infection

PRIMARY IMMUNODEFICIENCIES
● Most of these disorders are caused by defects in a
single gene, and are extremely rare
● Vary in severity from mild to nearly fatal
● Loosely categorized as affecting either innate immunity
or adaptive responses and are often grouped by the
specific components of the immune system most
affected
*the earlier the mutation, the more severe the manifestation of
the disease and most likely fatal
● Combined immunodeficiency
○ Diseases resulting from an absence of T cells
or significantly impaired T cell function,
combined with some disruption of antibody
responses
● B-cell immunodeficiency
○ Range from absence of B cells, plasma cells,
immunoglobulins to absence of only certain
classes of Abs
○ Subject to bacterial infection but do well
against viral since T-cell branch is okay
● T-cell immunodeficiency
○ Can affect both humoral and cell mediated
● Primary immunodeficiencies are often detected early
in life
*can manifest after birth or as early as 6 months
SEVERE COMBINED IMMUNODEFICIENCY
● The most severe forms of CID
● These stem from genetic defects that lead to a virtual
or absolute lack of functional T cells in the
periphery
● Usually fatal at early years of life
○ Infant will have viral and fungal infections
○ Bacteria don’t show up until later because of
placental transfer of Abs from mother
○ Chronic diarrhea, pneumonia, lesions
● Many genetic defects can contribute to SCID
○ Usually defects that target the early steps of
hematopoiesis
● Molecular mechanisms that explain the occurrence of
SCID
○ Defective cytokine signaling in T cell
precursors, caused by mutations in certain
cytokines, cytokine receptors, or regulatory
molecules that control their expression
*cytokines are needed for immune cells to
mature
○ Premature death of the lymphoid lineage
due to accumulation of toxic metabolites
caused by defects in the purine metabolism
pathways
○ Defective V(D)J rearrangement in
developing lymphocytes, caused by
mutations in the genes for RAG1 and RAG2,
or other proteins involved in the
rearrangement process
○ Disruptions in pre-TCR or TCR signaling
during development, caused by mutations in
tyrosine kinases, adapter molecules,
downstream messengers, or transcription
factors involved in TCR signaling

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● Adenosine deaminase (ADA) deficiency
○ ADA catalyzes conversion of adenosine or
deoxyadenosine to inosine or deoxyinosine,
respectively
*these purines need to be metabolized or else
they will be accumulated and eventually
become toxic
○ Intracellular accumulation of toxic
adenosine metabolites, which interferes
with purine metabolism and DNA synthesis
● Reticular dysgenesis (RD)
○ Initial stages of hematopoietic stem cell
development are blocked by defects in the
adenylate kinase 2 gene (AK2), favoring
apoptosis of myeloid and lymphoid
precursors and resulting in severe
reductions in circulating leukocytes
MHC DEFECTS
● A failure to express MHC molecules can lead to
general failures of immunity that resemble SCID
without directly impacting lymphocytes themselves
● Bare-lymphocyte syndrome
○ Caused by mutation in the TAP genes which
are vital to antigen processing and
presentation by class I MHC molecules
○ Failure to train T cells correctly, it affects both
B and T cells
DIGEORGE SYNDROME
● Decreased or absent thymus
● Results from deletion of region on chromosome 22
in developing embryo, developmental anomaly
● Lowered T cell numbers, results in B cells not
producing sufficient antibodies
● DGS patients present with symptoms of
immunodeficiency, hypoparathyroidism, and
congenital heart anomalies
WISKOTT-ALDRICH SYNDROME
● X-linked disorder
○ Results in issues with cytoskeleton
components in hematopoietic cells
● Clinical manifestations usually appear early in the first
year of life, eczema and thrombocytopenia are both
common
*if platelet count is low, patient is prone to bleeding
● Humoral defects, including lower than normal levels
of IgM, as well as impaired cell-mediated immunity,
are also common features
● WAS patients often experience recurrent bacterial
infections, especially by encapsulated
● Treated with passive antibodies or stem cell
transfer
● Can result in fatal infection or lymphoid malignancy
X-LINKED HYPER-IGM SYNDROME
● Deficiency of IgG, IgE, and IgA but elevated levels of
IgM
● Defect in T cell surface CD40L
○ This is needed for interaction between TH and
B cell for class switching for T dependent
antigens
○ T independent antigens are not affected
therefore there is production of IgM
HYPER-IGE SYNDROME (JOB SYNDROME)
● Caused by an autosomal dominant mutation in the
STAT3 gene
○ Its absence is thought to lead dysregulation of
TH pathway development and may be the
reason for overproduction of IgE
○ Depressed TH17 responses, which are
important for clearance of fungal and
extracellular bacterial infections, explain the
susceptibility of these patients to C. albicans
and S. aureus
● Skin abscesses, pneumonia, eczema, and facial
abnormalities
● High # of eosinophils and IgE
○ But don’t show increased allergies
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X-LINKED AGAMMAGLOBULINEMIA
● Bruton’s agammaglobulinemia
● Caused by a defect in Bruton’s tyrosine kinase,
which is required for signal transduction through the
BCR
○ B lymphocytes in these patients remain in
the pre-B stage, with heavy chains
rearranged but light chains in their germ-line
configuration
● Low levels of IgG and absence of other classes
● Recurrent bacterial infections

COMMON VARIABLE IMMUNODEFICIENCY

● Reduction in the levels of one or more antibody
isotype and impaired b-cell responses to antigen, all
with no other known cause
● Can manifest in childhood or later in life, when it is
sometimes called late-onset hypogammaglobulinemia CHEDIAK-HIGASHI SYNDROME
● Autosomal recessive disease
● Inheritance can follow autosomal recessive or
● Phagocytes don't have ability to kill bacteria
autosomal dominant patterns, although most cases
○ Mutations in LYST gene that cause defects in
are sporadic
the transport of proteins into lysosomes as
well as for controlling lysosome size,
SELECTIVE IGA DEFICIENCY
● Most of these affected are asymptomatic (up to 70%), movement and function
whereas others may suffer from an assortment of ○ Affected phagocytes produce giant
serious complications granules, a diagnostic hallmark, but are
● Problems such as intestinal malabsorption, allergic unable to kill engulfed pathogens
disease and autoimmune disorders can be ● Neutropenia as well as impairments in T cells, NK cells,
associated with low IgA levels and granulocytes
● Inability of IgA-expressing B cells to undergo normal
differentiation to the plasma cell stage MENDELIAN SUSCEPTIBILITY TO MYCOBACTERIAL
DISEASES
*prone to recurrent respiratory, digestive or intestinal infections
● Autosomal recessive trait – results from inbreeding
*recessive trait in the family manifests in inbreeding
LEUKOCYTE ADHESION DEFICIENCY
● Associated with defects in either the IFN-γ pathway
● Integrin proteins needed for adhesion and cellular
(e.g., IFNγR or the related STAT signaling molecule) or
interaction
IL-12/23 signaling pathway (e.g., IL-12, IL-12R, an
○ Defect limits recruitment of cells into areas
the associated TYL2 signaling molecule)
of inflammation
○ These pathways are particularly important
● Causes susceptibility to infection with both gram-
for clearing intravesicular infections
positive and gram-negative bacteria as well as
*Important in killing engulfed bacteria
various fungi
*patients more susceptible to tuberculosis
● Impairment of adhesion of leukocytes to vascular
endothelium limits recruitment of cells to sites of
inflammation

REDUCTION IN NEUTROPHIL COUNT

● Low concentration – granulocytopenia or neutropenia
● Congenital neutropenia
CHRONIC GRANULOMATOUS DISEASE ○ Frequent bacterial infections
● Prototype of immunodeficiency that impacts
● Acquired neutropenia
phagocytic function and arises in at least two forms
○ Certain drugs or chemotherapy can cause
○ X-linked form in about 70% of patients
this
○ Autosomal recessive from found in the rest
○ Autoimmune disorder – destruction of
● Defect in the NADPH oxidative pathway by which
neutrophils
phagocytes generate superoxide radicals and other
*prone to infections
reactive compounds that kill phagocytosed pathogens
● Infection by bacterial and fungal pathogens, as well as
COMPLEMENT DEFICIENCIES
excessive inflammatory responses that lead to the ● Fairly common
formation of granulomas (a small mass of inflamed ● Mostly associated with bacterial infections or
tissue) immune-complex diseases
○ Deficiency in properdin, which stabilizes the
C3 convertase in the alternative pathway, is

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 associated with increased risk of infection
with species of Neisseria
■ These types of bacterial infection are
also more common in those with
defects in C5-C9
○ Defects in mannose binding lectin (MBL)
result in an increased susceptibility to a
variety of infections by bacterial or fungal
agents
*patients are prone to meningitis
● gp120 determines viral tropism by binding to target cell
receptors, while gp41 mediates fusion between viral
and cellular membranes
*the cost of attachment (gp120) is always greater than the cost
of fusion/penetration (gp41)
● Recognizes CD4 antigen on T cell

TREATMENTS FOR IMMUNODEFICIENCIES

● Replacement of missing protein
○ Administering immunoglobulin
○ Express genes in vitro (in bacteria) for
cytokines
● Replacement of missing cell type
○ Bone marrow transplantation
● Replacement of missing or defective gene
○ Gene therapy
■ Still far out from clinical use ● HIV genotypes
■ Can be corrected in vitro and then ○ HIV1 – main causative agent for AIDS
introduce cells back into patient ■ Many different subtypes
■ Probably evolved from Simian
ACQUIRED IMMUNODEFICIENCY immunodeficiency virus and
● No genetic component transferred to humans during the
● Examples: “bushmeat trade” in early 1900s
○ Hypogammaglobulinemia – unknown cause, ○ HIV-2 – cousin to HIV1 but diseases
different from genetic condition progresses slowly, if at all
○ AIDS caused by HIV ● The typical course of an HIV infection
○ Malnutrition

SEVERE MALNUTRITION
● Affects both innate and adaptive immunity
● Sustained periods with very low protein-calorie
diets (hypoproteinemia) are associated with
depression in T-cell numbers and function, although
deleterious b cell effects may take longer to appear
● Insufficiency in micronutrients, such as zinc, ascorbic
acid, likely contributes to the general
immunodeficiency and increases susceptibility to
opportunistic infection

THE GLOBAL AIDS EPIDEMIC

*acute phase: fever, respiratory infection and will get better

*as virus continues to proliferate it impairs CD4 T cells
*prone to a lot of opportunistic infections
*takes a long time for AIDS to manifest
● HIV treatment

HIV EPIDEMIC IN THE PHILIPPINES

*remember common suffixes

HIV
● Retrovirus (Lentavirus genus)
*army that reverse transcribe its RNA to DNA and will be
incorporated in the host’s DNA
● Viral envelope derives from host
○ Can have class I or class II MHC