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Immunodeficiency Disorders מחלות חסר אימונולוגיות. 0. 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

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Immunodeficiency Disorders

מחלות חסר אימונולוגיות

origins of immunodeficiency


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 מערכת החסון, או נזק למולקולה בעלת תפקוד חסוני.
  • Secondary or acquired
    • A loss of previously functional immunity due to infection, toxicity, radiation, splenectomy, aging, malnutrition, etc.
    • נזק למערכת חסון תקינה כתוצאה מהדבקה, רעילות, קרינה, אבוד טחול, גיל, תזונה לקויה ועוד.
primary immunodeficiencies
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


Infectious Consequences of Immunodeficiencyמשמעות 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)
  • מחסור בנוגדנים, פאגוציטוזה לא תקינה ומחסור בחלבוני משלים, קשורים 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
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 antibody-mediated 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
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
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
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 class-switch in presence of T cells

Molecular Defect - mutations in activation-dependent cytidine deaminase (AID).

treatment of b cell disorders
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

defect in t cells di george s syndrome dgs
Defect in T CellsDi 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
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
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 s evere c ombined i mmuno d eficiency
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 g chain
Some Heteromeric Cytokine Receptors Share at least the g Chain

e.g. the IL-2R family utilizes the same g chain.

scid i common chain
SCID I - Common  chain
  • 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
SCID II - Adenosine DeaminaseDeficiency (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



scid iii deficiencies in jak 3 kinase
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
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


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
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
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
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
Diagnosing a primary immunodeficiency
  • Detect a history of recurrent infections
  • Hematology-measures total RBC and WBC cell numbers
  • Facs analysis-determines the numbers of each lymphocyte subset ie. CD4:CD8 T cells, B cells, neutrophils etc.
  • Measurement of serum immunoglobulins
  • Specialized testing
    • T cells-proliferation in response to stimuli
    • B cells-induced antibody production
    • Phagocytes-engulfment
    • Complement-CH50 the dilution of serum required to lyse 50% of ab-coated RBC
complement deficiencies


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


Causes of Acquired Immunodeficiency
  • Cancer (immunoproliferative diseases)
  • Cytotoxic drugs or radiation
  • Malnutrition
  • Splenectomy
  • Immunosuppressive therapies
  • Stress/emotions
  • Aging (thymic atrophy)
  • Infection (HIV )
secondary immunodeficiency s
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 antibody-mediated and cell-mediated immune systems