Immunodeficiency Disordersמחלות 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 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=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)

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

• 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

– 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).

X-linked Agammaglobulinemia(Bruton’s Agammaglobulinemia)

Hyper-IgM SyndromeA 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 inHyper IgM Immuonodeficiency

Activation-Induced Cytidine Deaminase Deficiency (AICD)

Autosomal recessiveMale and FemaleDiagnosis - 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

Agammaglubulinemia - Monthly injections of antibody, intravenous gammaglubin “IVIG”

Hyper IgM Syndrome - Bone marrowtransplant at early age. IVIG, management of infections with antibiotics

Immunodeficiency Syndromes

T Cell Deficiencies

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

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.

• 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

SCID - Severe Combined Immunodeficiency

Some Heteromeric Cytokine Receptors Share at least the Chain

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

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, 2

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 complexAbsence 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 DeficiencyAbsence of leukocyte adhesion molecules (CD18, 2 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 infections2. Hematology-measures total RBC and WBC cell

numbers3. Facs analysis-determines the numbers of each

lymphocyte subset ie. CD4:CD8 T cells, B cells, neutrophils etc.

4. Measurement of serum immunoglobulins5. Specialized testing

1. T cells-proliferation in response to stimuli2. B cells-induced antibody production3. Phagocytes-engulfment4. 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

• 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 antibody-mediated and cell-mediated immune systems