Dire dawa University
College of Medicine and health sciences
Department of Medical Laboratory Sciences
Chapter 9
Immunodeficiency
Menberu W. (BSC, MSc), D’pt of MLS, CMHS,DDU
April, 2024
Dire dawa, Ethiopia
6/10/2024 Menberu W. 1
Immune Disorder
• An immune disorder is a dysfunction of the
immune system
• Immune dysfunction occurs as a result of improper
regulation that allows the immune system to
– Either attack something it shouldn’t or
– Fail to attack something it should
• ID cause abnormally low activity or over activity of
the immune system
IMMUNEDEFICIENCY
DISORDERS
Introduction
• Like any complex multicomponent system, the
immune system can be subject to failures of some
or all of its parts.
• These failures can have consequences.
• When the system loses its sense of self and
begins to attack the host’s own cells, the result is
autoimmunity.
• When the system errs by failing to protect the host
from disease causing agents, the result is
immunodeficiency.
Introduction
• Two broad categories of immunodeficiency
disorders are:
1. primary immunodeficiency.
2. Secondary immunodeficiency
1. Primary immunodeficiency
Immunodeficiency resulting from an inherited
genetic or developmental defect in the immune
system is called a primary immunodeficiency or
congenital immunodeficiency.
Congenital immunodeficiency syndromes are under
diagnosed.
Basic knowledge of embryology of immunity is
essential to understand most congenital syndromes
1. Primary defects of Ab production
Of all of the primary immunodeficiency
diseases, those affecting antibody production
are most frequent
Selective absence of serum and secretory IgA is
the most common defect, with rates ranging
from 1/333 to 1/18,000 persons among different
races.
Range of Normal serum Ig
• IgG - 620–1,400 mg/dL
• IgA - 80–350 mg/dL
• IgM -45–250 mg/dL
• IgE – 5-10 mg/ml
A. X- linked agammaglobulinemia (XLA)
• Patients XLA, or Bruton agammaglobulinemia, have
- profound defect in B-lymphocyte development
- severe hypogammaglobulinemia
- absence of circulating B cells
- small to absent tonsils
- no palpable lymph nodes
• The abnormal gene in XLA maps to q22on the long
arm of the X chromosome and encodes the B-cell
protein tyrosine kinase Btk (Bruton tyrosine kinase)
B. Common variable immunodeficiency
• hypogammaglobulinemia with phenotypically
normal B cells
• Equal sex distribution
• No identified molecular diagnosis
X-linked hyper-IgM syndrome (XHM)
• Deficiency of IgG, IgA, and IgE – elevated levels of IgM
• Normal numbers of B cells
• Both X-linked & acquired
• Autoantibodies to PMNs, platelets, & rbc
• Failure to produced germinal centers
• Defect is in gene encoding CD40L (CD154) required for B cell
responses to T-dependent antigens.
Class switching and memory B cells are not formed.
C. Selective IgA deficiency
• Most common of primary antibody deficiencies
• Isolated or near absence of serum or secretary
IgA (<10mg)
• Occasionally associated with ill health
• Basic defect is unknown
Treatment of B cell defects
• Intravenous immunoglobulins
• Stem cell transplant
2. Primary defects of Cellular immunity
In general, patients with defects in T-cell
function have infections or other clinical
problems that are more severe than in patients
with antibody deficiency disorders.
These individuals rarely survive beyond infancy
or childhood
A. Thymic hypoplasia ( DiGeorge syndrome)
• Hypoplasia or aplasia of the thymus and
parathyroid glands
• The diagnosis is often first suggested by
hypocalcemic seizures during the neonatal period
3. Severe combined immunodeficiency(SCID)
The syndromes of SCID are caused by diverse
genetic mutations that lead to absence of all
adaptive immune function and, in some, a lack
of natural killer (NK) cells.
Patients with this group of disorders have the
most Severe immunodeficiency.
• Wiskott -Aldrich syndrome (WAS)
- defective gene encodes for CD43 required for cytoskeletal reorganization -
needed for T cells to deliver cytokines & signals - cell counts are normal
• Bare lymphocyte syndrome (MHC class II)
- Impairment of MHC gene transcription
– CD4 cells fail to develop
• Bare lymphocyte syndrome (MHC class I)
•Mutation in TAP genes - necessary for ag processing in CD8+-
mediated immunity
• ZAP-70 Deficiency
T cell signal transduction defect
• RAG mutations
T and B cell development defect
Combined immunodeficiency (CID)
• CID is distinguished from SCID by the presence
of low but not absent T-cell function.
• Similar to SCID, CID is a syndrome of diverse
genetic causes.
• Patients with CID have recurrent or chronic
pulmonary infections, failure to thrive, oral or
cutaneous candidiasis, chronic diarrhea, recurrent
skin infections
Treatment of Combined defects
• Good supportive care including prevention and
treatment of infections is critical while patients await
more definitive therapy
• Immunoglobulins
• Transplant
4. Disorders of phagocytic function
• Neutrophils are particularly important in protecting
the skin, mucous membranes, and lining of the
respiratory and GI tracts as part of the 1st line of
defense against microbial invasion.
• Disorders of phagocyte function should be
considered if results of initial screening tests are
normal and the patient has had recurrent or unusual
bacterial infections
• Chediak-Higashi syndrome
• Myeloperoxidase deficiency
• Chronic granulomatous disease
5. Complement deficiency
• is an ID of absent or suboptimal functioning of one
of the complement system proteins.
• The disorders can be divided into two categories:
1. Disorders of the proteins that act to inhibit the
complement system (such as C1-inhibitor) can lead
to an overactive response, causing conditions such
as hereditary angioedema and hemolytic-uremic
syndrome.
2. Disorders of the proteins that act to activate the
complement system (such as C3) can lead to an
underactive response, causing greater susceptibility
to infections.
Clue about Nature of immunodeficiency
• Repeated pyogenic infections (tonsillitis, otitis media,
pneumonia, diss. Impetigo)
– Atrophied peripheral lymph nodes and tonsils
– B lymphocyte deficiency
• Severe mycotic infections, disease after live vaccine
– T lymphocyte deficiency
• Abscess formation (staph, serratia, aspergillus)
– Neutrophil deficiency
• Repeated Neisseria infection
– Complement deficiency
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2. SECONDARY IMMUNODEFICINCY
Secondary immunodeficiency, also known as acquired
immunodeficiency, is the loss of immune function that
results from exposure to an external agent, often an
infection.
Although several external factors can affect immune
function, by far the most well-known secondary
immunodeficiency is acquired immunodeficiency
syndrome (AIDS).
Causes of secondary immunodeficiency
• Systemic disorders
– Ig hypercatabolism
• Surgery
– Excess loss of Ig • Malignancies
– Renal insufficiency
– B cell and plasma cell
– Extensive burns
malignancies
• Drug induced
– Cytotoxic – Thymoma
– Glucocorticoids – Non Hodgkin’s lymphoma
–
–
Antimalaria agents
Captopril
• Infectious diseases
– Carbamazepine
– HIV
– Phenytoin – Congenital rubella
– Alcohol, opiates – Congenital toxoplasmosis
– Epistein-Barr virus
• Malnutrition
– PEM
– Zinc
– Vitamins (pyridoxine, folic acid,
vit A)
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Acquired hypogammaglobulinemia
• Confused with common variable immunodeficiency
(genetic)
• Cause is unknown
• Sx –
– Recurrent infections
– Young adults
– Low but detectable level Ig
– T-cell usually normal
– Deficiency of Ig in new borne but improves
• Tx – Ig
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Agent induced immunodeficiency
• Cause is chemicals, biological agents
– Drugs for autoimmune diseases, steroids
– Post transplant – cyclosporine A
– Radiation therapy
• Higher risk of infection (chronic infections DM)
• Tx – close follow up and early treatment of infections
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Acquired Immunodeficiency Syndrome
HIV
• 1981 - First AIDS cases in USA
– 5 PCP and 26 KS cases among homosexuals
– Subsequently it was detected also among IDU and
hemophilics
• 1983 - HIV was isolated from a pt with PGL
and demonstrated as the cause of AIDS in
1984
• 1985 - ELISA was developed and used for
detection of the epidemiologic scope
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Role of T helper cells
• Normal count 700-1200cells/ml
– Induction of CTL maturation and function
– Induction of Natural killer cells function
– induction of B cells differentiation and function
– activation of macrophages
– secretion of growth factors for lymphoid cells
– secretion of hematopoietic colony stimulating
factors
– central for both cell mediated and humeral immune
arms
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ID by HIV contd..
• Direct effect of viral component on Th cells
• Functional disturbance of CD4 (low Ag detection)
• Low IL-2 expression
• Alter Th homing (increase migration to LN)
• Apoptosis of Th via caspase
• Cytopathic effect by CD8 cells
• Low production of immunomodulatory by Th
• Disturbing proper CD8 maturation
• Increase AAMQs, B cell hyperactivation
• NK= impaired cytolytic
Immune reconstitution inflammatory
syndrome
Development of clinical manifestations of a
previously sub-clinical opportunistic infection
and/or paradoxical worsening of active infection
despite appropriate treatment.
It occurs in 11-45% of HIV TB coinfected and on tx.
Occurs usually within 3 months of starting ART
Reflects a restored, protective, pathogen-specific
immune response,
Not ART treatment failure
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