Transcript Humoral Immunodeficiencies

Immunodeficiency Disorders
‫מחלות חסר אימונולוגיות‬
Origins of Immunodeficiency
• Primary or Congenital
‫ראשוני או מולד‬
– Inherited genetic defects in immune cell development or
function, or inherited deficiency in a particular immune
molecule
‫– פגם גנטי מורש הגורם להתמינות לא תקינה או תפקוד לקוי של תאי‬
.‫ או נזק למולקולה בעלת תפקוד חסוני‬,‫מערכת החסון‬
• Secondary or acquired
– A loss of previously functional immunity due to
infection, toxicity, radiation, splenectomy, aging,
malnutrition, etc.
‫ אבוד‬,‫ קרינה‬,‫ רעילות‬,‫– נזק למערכת חסון תקינה כתוצאה מהדבקה‬
.‫ תזונה לקויה ועוד‬,‫ גיל‬,‫טחול‬
Primary Immunodeficiencies
• Primary=Genetically determined
• More than 100 disorders identified
• Most are B cell deficiencies
– Incidence ranges by disorder
• IgA deficiency 1:333
• Agammaglobulinemia 1:50,000
• SCID 1:250,000
• Seen more in infants
– 5:1 male-to-female predominance in
children
– 1:1.4 male-to-female in adults
Infectious Consequences of
Immunodeficiency
‫משמעות חסר חסוני לגבי הדבקות בפתוגנים‬
• Antibody deficiency, Phagocyte deficiencies, or Complement
protein deficiencies are associated with recurrent infections with
extracellular pyogenic bacteria (pneumonia, otitis media, skin
infections)
‫ קשורים‬,‫ פאגוציטוזה לא תקינה ומחסור בחלבוני משלים‬,‫• מחסור בנוגדנים‬
.‫להדבקות בחידקים חוץ תאיים גורמי מוגלה‬
• Deficiency in Cell-mediated immunity is associated with
recurrent or chronic viral, fungal, or protozoal diseases.
,‫חוסר של מערכת חסון תאית מלווה בהדבקות חוזרות או כרוניות בוירוסים‬
.)‫פטריות או פתוגנים חד תאיים (למשל טוקסופלסמה‬
•
Primary B cell Deficiencies
• Genetic disorders of the B lymphocytes
• Approximately 70% of primary immunodeficiencies
Not enough Ig or too much Ig
• X-Linked Agammaglobulinemia (XLA)
• Hyper IgM Syndrome
• Selective IgA deficiency
– Occurs in 1:600-1:800 people
• Development of anti-IgA antibodies may lead to
severe anaphylactic reactions with blood
transfusions
X-linked Agammaglobulinemia
(Bruton’s Agammaglobulinemia)
– B cells do not differentiate. Mutation in Bruton’s
tyrosine kinase (Btk) required for B cell development.
- B cells absent in peripheral blood.
- T cell numbers and function are normal
– no antibodies are produced, thus no antibodymediated immunity
– cell-mediated immunity is OK
– affects males only
– Symptoms at 9 mo. to 2 yr of age
– Treat with intravenous immunoglobulin (IVIG).
Hyper-IgM Syndrome
A syndrome characterized by very low serum IgG, IgA
and IgE but extremely high levels of IgM.
X-linked - CD154 (CD40 Ligand) Deficiency
Autosomal Recessive -Activation-Induced Cytidine
Deaminase Deficiency (AICD)
CD154 (CD40 Ligand) Deficiency
Diagnosis - Males become
symptomatic after 6-9
months. Prone to pneumonia,
have profound neutropenia,
and very small lymph nodes
and tonsils. B cells and T cell
numbers are normal.
Molecular Defect - mutation in
CD154 or CD40 Ligand.
- found on the surface of
activated helper T cells.
Interacts with CD40 on
surface of B cells.
- Cross-linking of CD40 by
CD40L in the presence of
cytokines causes B cells to
undergo proliferation and
isotype switching.
Defective T-B interaction in
Hyper IgM Immuonodeficiency
Activation-Induced Cytidine
Deaminase Deficiency (AICD)
Autosomal recessive
Male and Female
Diagnosis - Serum IgG, IgA, and IgE are very low.
Serum IgM elevated and polyclonal.
-Patients are generally older and not susceptible to
pneumonia.
-Normal numbers of B cells but are not able to classswitch in presence of T cells
Molecular Defect - mutations in activation-dependent
cytidine deaminase (AID).
Treatment of B cell disorders
Agammaglubulinemia - Monthly injections of
antibody, intravenous gammaglubin “IVIG”
Hyper IgM Syndrome - Bone marrow
transplant at early age. IVIG,
management of infections with antibiotics
Immunodeficiency Syndromes
T Cell Deficiencies
Defect in T Cells
Di George’s Syndrome (DGS)
A disease that results from hypoplasia (partial loss) or aplasia (complete loss) of
thymus and parathyroid glands, therefore no T cells. Relatively common
(1/4000 live births), affect both male and female
Diagnosis - Spectrum of developmental abnormalities: cardiac outflow abnormalities
(congenital heart disease) , hypoplasia of the parathyroid and thyroid glands,
cleft palate and unusual facies. Normal Ig levels.
Molecular Defect - Gene Tbx1 (transcription factor) on chromosome 22q11 is
defective in most cases. Causes defects in 3rd and 4th pharyngeal pouches
during embryogenesis
Clinical spectrum and effect on thymus is highly variable
Complete (rare) : Severe T cell lymphopenia. Increased susceptibility to
pneumonia (P. carinii), oral candidiasis, diarrhea, failure to thrive.
Mild (common) : present in adults as chronic sinusitis/ bronchitis
Di George’s Syndrome
Facies: Micrognathia, low set ears, anti-mongoloid slant to eyes,
fish-shaped mouth, hypertelorism, narrow philtrum
Treatment of Di George’s
Syndrome
• Partial form - generally don’t need
immunological treatment
• Complete form
– Thymic epithelial explants
• Culture mature thymic epithelial cells and
transplant into patient.
SCID - Severe Combined
Immunodeficiency
• A fatal syndrome of diverse genetic causes
characterized by profound deficiencies in both T and B
cells
• Diagnosis
– Early onset <6mos
– Frequent episodes of diarrhea, pneumonia, otitis,
sepsis, cutaneous infections
• Molecular Defects
– Quite diverse, although several common etiologies
occur
• Common (gamma) chain - X-linked
• Adenosine Deaminase
- autosomal recessive
• Jak 3 kinase
- autosomal recessive
Some Heteromeric Cytokine Receptors
Share at least the  Chain
e.g. the IL-2R family utilizes the same  chain.
SCID I - Common  chain
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Most common etiology of SCID - 46% of cases
in the US
X-linked recessive ONLY in males
Abnormal gene was identified as the common 
chain that is shared by several cytokine
receptors - IL-2, IL-4, IL-7, IL-9, IL-15, IL-21
Lack T cells and NK cells
Elevated B cell numbers but are non-functional
“Bubble Boy”-David Vetter lived for 12 years in
a plastic germ-free bubble
SCID II - Adenosine Deaminase
Deficiency (ADA)
• Autosomal recessive
• 15% of US cases
• ADA is an enzyme that is involved in purine metabolism
– Irreversibly deaminates adenosine (nucleoside from food
and nucleic acids) converting to inosine by removing amine
group
• Patients get accumulation of adenosine and 2’-deoxyadenosine
in thymocytes and peripheral B cells
– Inhibits DNA synthesis and leads to destruction of cells
Adenosine
Inosine
SCID III - Deficiencies in
Jak-3 Kinase
•
Autosomal recessive
•
JAK-3 kinase is the
only known signaling
molecule associated
with the common 
chain
•
No T cells and NK cells
•
B cells present but
non-functional
Treatment of SCID
• Bone marrow transplantation
• Gene therapy
– ADA was first genetic defect that was attempted
– 9 infants received autologous bone marrow that was
retrovirally transduced with common  chain
– Initially successful-full correction of T and NK cell defect
• Enzyme replacement therapy
– For ADA
Phagocyte Deficiencies
• Chronic Granulomatous Disease
– NADPH oxidase defect
– Intracellular and extracellular infections, granulomas
• Chediak-Higashi Syndrome
– Abnormal lysosome formation
– Intracellular and extracellular infections, granulomas
• Leukocyte Adhesion Deficiency
– Absence of leukocyte adhesion molecules (CD18, b2
integrin)
– Defective migration of phagocytes (neutrophils) into
infected tissues
– Widespread pyogenic bacterial infection
Chronic Granulomatous Disease
(CGD)
Neutrophils require a set of enzymes to produce reactive oxygen species
to destroy bacteria after their phagocytosis. Together these enzymes
are termed "phagocyte NADPH oxidase" (phox). Defects in one of
these enzymes can all cause CGD of varying severity, dependent on
the defect. There are over 410 known defects in the enzyme complex
Absence of respiratory burst (conversion of intracellular oxygen to
hydrogen peroxide, oxidized halogens, superoxide and hydroxyl
radicals) in neutrophils and monocytes-impaired bactericidal killing
What are Granulomas?
Chronic inflammation with a characteristic
pattern of a central area of phagocytic cells
surrounded by activated lymphocytes.
Macrophages fuse to form giant cells in the
center
Serves to “wall off” pathogens that resist
destruction.
In CGD get continuous granuloma formation
because neutrophils cannot clear microbes
Nasal inflammation/cellulitis and neck
granuloma in an X-linked CGD patient.
Leukocyte Adhesion Deficiency
Absence of leukocyte adhesion molecules (CD18, b2 integrin)
Defective migration of phagocytes (neutrophils) into infected tissues
Inherited Immunodefiency:
Summary
X linked SCID (common gamma chain)
T cell deficiency )absence of thymus DiGeorge’s syndrome(
Antibody Deficiencies XLA (Btk-/-) Hyper IgM (CD40L-/-)
Deficiencies in Phagocytosis/killing:
Respiratory Burst (CGD)
Diagnosing a primary
immunodeficiency
1. Detect a history of recurrent infections
2. Hematology-measures total RBC and WBC
cell numbers
3. Facs analysis-determines the numbers of
each lymphocyte subset ie. CD4:CD8 T cells,
B cells, neutrophils etc.
4. Measurement of serum immunoglobulins
5. Specialized testing
1. T cells-proliferation in response to stimuli
2. B cells-induced antibody production
3. Phagocytes-engulfment
4. Complement-CH50 the dilution of serum
required to lyse 50% of ab-coated RBC
Complement Deficiencies
• Single component deficiencies
– Example: C3 deficiency
• Hereditary Angioedema
– C1 Inhibitor deficiency
• C5,C6,C7,C8, or C9 deficiency
– Recurrent bacterial meningitis due defective
membrane attack complex
Causes of Acquired
Immunodeficiency
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Cancer (immunoproliferative diseases)
Cytotoxic drugs or radiation
Malnutrition
Splenectomy
Immunosuppressive therapies
Stress/emotions
Aging (thymic atrophy)
Infection (HIV )
Secondary Immunodeficiency's
– viral infections
• many viruses are capable of infecting and killing
lymphocytes, thus effectively lowering the
immune response
• human immunodeficiency virus (HIV) infects and
destroys TH cells, diminishing both the antibodymediated and cell-mediated immune systems