Lecture 20: Immune Deficiencies

Question 1

The infections associated with immunodeficiences have what typical features

Answer 1

• They are often chronic, severe, or recurrent
• They are not responsive well to an antibiotic therapy
• The microbes involved may be atypical or opportunistic

Question 2

What are Primary imune deficiences (PIDs)

Answer 2

• Oftne clinically manifested during the first years of life (after 5-6 months):
  
  • Because of Maternal IgG being in blood till about month 6, immune deficiences are not detected in the newborn

Question 3

Maternal IgG in the infant begins to disappear after birth and has a half life of

Answer 3

25-30 days

Question 4

What are the warning signs of Immunodefieciency disorder

Answer 4

• Medical History:
  
  • Eight or more ear infections in one year
  • Two or more serious sinus infections in one year
  • Two or more bouts of pneumonia in one year
  • Two or more deep-seated infections, or infections in unusual areas
  • Recurrent deep skin or organ abscesses
  • Need for IV antibiotic therapy to clear infection
  • Infections with unusual or opportunistic organisms
  • Family history of primary immunodeficiency

Question 5

Adenosine Deaminase Deficiency (ADA) is considered a combined immune deficiency affecting:

Answer 5

• B cells
• T cells
• NK cells

Question 6

X-linked Agammaglobulinemia

Answer 6

• an inherited immunodeficiency disease caused by mutations in BTK gene coding the Bruton Tyrosine Kinase (BTK)
• X-linked
• Diagnosis: in 5-6 month old
• Caused by defect in rearrangement of the Ig Heavy chain genes
• Early B-cell development is arrested at the pre-B cell stage → circulating B cells are usually absent or present in very low numbers (thus plasma cells are absent)
• IgG, IgA, and IgM are low or totally absent
• The Reticuloendothelial and lympohid organs in which B cells proliferate, differentiate, and are stored are poorly developed or absent:
  
  • Spleen
  • Tonsils
  • Adenoids
  • Peyer patches
  • Peripheral lymph nodes

Question 7

Autosomal recessive Agammaglobulinemia

Answer 7

Question 8

Common Variable Immune Deficiency

Answer 8

• A heterogeneous group of diseases associated with hypogammaglobulinemia
• Both mlaes and females are equally affected (genetic inheritance pattern is not completely determined)
• Age of diagnosis
  
  • greater than 2 years of age (can be in 20s or 30s)
• Onset
  
  • is frequently after 4-5 years of age (between 2-80 years)
• Low IgG, IgA, Normal/Low IgM
• All paitents have hypogammaglobulinemia
  
  • all isotypes or IgG only
• About 1/3 of patients have low B cells
  
  • T cell deficience may alos occur
• may be caused by:
  
  • Defects in B-cell formation
    
    • (inherited)
  • Abs against B cells (immune targeting)
    
    • (inherited)
• Susceptible to reccurent bacterial infections
  *

Question 9

IgA deficiency

Answer 9

• incidence is relatively high
  
  • 1:700
• Diagnosis
  
  • often remain asymptomatic
• Prevalence may be higher in male patients
• Pathogenic mecahnism involves IgA secreting B cells:
  
  • Disorder of maturation or Terminal differentiation
• Low IgA, normal IgG and IgM

Question 10

Hyper IgM syndromes (HIGM)

Answer 10

• A group of diseases characterized by imparied Ig class switching and somatic hypermutation
• Patients with these sysndromes have an increased susceptibility to bacterial infection
• Normal numbers of peripheral B cells but low memory B cells
• Genetics:
  
  • X-linked
    
    • CD40L deficiency is responsible for 2/3 of cases of HIGM
      
      • Without CD40L you can not have class switching and somatic hypermutation in B cells
  • Autosomal CD40 deficiency
    
    • Deficiency acounts for 1/3 of cases of HIGM
• High IgM, Low IgG and IgA

Question 11

Isolated IgG subclass Deficiency

Answer 11

• Characterized by decreased concentrations of one or more IgG subclass
• Total IgG, IgM, IgA, and IgE are normal
• usually asymptomatic
• Low levels of IgG₂ are frequent in children (association with poor responses to polysaccharide Ags)
• The IgG₄ vary widely and many healthy people have no IgG₄
• These deficiencies may be associated with recurrent viral/bacterial infections, frequently involving the respiratory tract

Question 12

Transient Hypogammaglobulinemia of Infancy

Answer 12

• Low IgG/IgA, IgM can be normal
• Maternal IgG in the infant disappears after birth with a half-life of 25-30 days
• Intrinsic IgG production usually begins immediately after birth
• In transient hypogammaglobulinemia of infancy, intrinsic Ig production is delayed for up to 36 months
  
  • Results in low IgG and IgA concentrations, but IgM concentration may be normal or low
• increased susceptibility to sinopulmonary infections
• in the majority of patients Ig concentrations normalize between 2 and 4 years of age

Question 13

Wiskott-Aldrich Syndrome

Answer 13

• Low IgM; IgG normal, IgA and IgE are elevated
• X-linked recessive syndrome with progressive decrease in T cells
• The defect appears to be in a cytoskeletal protein called Wiskott Aldrich Syndrome Protein (WASP):
  
  • WASP expression is limited to cells of hematopoietic lineage
• Clinical manifestations:
  
  • Thrombocytopenia
  • Small platelets
  • Platelet dysfunction
  • Eczema
  • Susceptibility to infections
• in infants:
  
  • prolonged bleeding from circumcision site
  • Bloody diarrhea
  • Excessive bruising
• Recurrent infection by Encapsulated Bacteria
• at risk for:
  
  • Autoimmune diseases
  • Cancer

Question 14

Severe Combined Immune Deficiency (SCID)

Answer 14

• Associated with profound Deficiencies of T-cell and B-cell funciton (sometimes NK cell function)
• Typically demonsrate severe Lymphopenia
• At risk abortion of pregnancy:
  
  • Inability to reject the maternal T cells that T cells that cross into the fetal circulation in utero
• Characterized by
  
  • SEVERE OPPORTUNISTIC INFECTIONS
  • or by chronic diarrhea and failure to thrive

Question 15

Defects in T-Cell Function

Question 16

Question 17

Question 18

Question 19

Question 20

Question 21

Question 22

Question 23

Common Gamma Chain Deficiency (gammaC or IL-2Rgamma)

Answer 23

• Most common form of SCID
• X-linked
• Gene encodes Gamma-Chain shared by the T-cell gowth factor receptor (IL-2Rgamma) and other growth factor receptors
• There are no funcitonal B cells since T cells are unable to help
• T^-,B⁺,NK^-
• Susceptiable to:
  
  • Opportunistic fungal infections, chronic diarrhea, skin, mouth, and throat lesions

Question 24

Adenosine Deaminase Deficiency (ADA)

Answer 24

• Autosomal Recessive trait
• mutations in ADA gene
• second most common form of SCID
• ADA is essential for metabolic funciton of various cells especialy T cells
• ADA leads to an accumulation of toxic metabolic by-products adenosine and deoxy-ATP → lymphocytes die
• Susceptiablity to:
  
  • Opportunistic fungal infections, chronic diarrhea, skin mouth, and throat lesion
• T^-,B^-,NK^-

Question 25

Deficiency of Jak3

Answer 25

• Autosomal recessive trait
• Defect in IL-2 receptor signaling
• Susceptible to:
  
  • Opportunistic fungal infections
  • Chronic diarrhea
  • Skin, mouth, and throat lesions
• T^-,B⁺,NK^-

Question 26

DiGeorge Syndrome (DGS)

Answer 26

• T-Cell deficiency
• caused by abnormalities in embryogenesis
• Features:
  
  • Hypocalcemia (key feature)
  • Parathyroid hypoplasia
  • Thymic hypoplasia
  • malformation of outflow vessels of the heart
• Delation of 22q11 chromosome
• Diagnsosis:
  
  • Facial abnormalities
  • Major outflow tract defect of the hear or history of recurrent infections
• Susceptible to:
  
  • Oportunistic infections
    
    • Fungal
    • Viral
    • Protozoal
    • Recurrent with intracellular bacteria

Question 27

MHC Class I Deficiency

Answer 27

• Caused by inability of TAP1 molecules to transfer peptides to ER
• CD8⁺ cells are deficient
  
  • This leads to recurring viral infections
• CD4⁺ Are normal ^​
  
  • normal Ab production
• Normal DTH (delayed type hypersensitivity)

Question 28

Bare Lymphocyte Syndrome

Answer 28

• A rare recessive disease
• No MHC Class II expression on professional APCS
  
  • Gens for MHC class II on chromosome 6 are intact though
• Deficiency in CD4⁺ T cells
• Variable hypogammaglobulinaemia (mainly IgA and IgG2)
• Leas to recurrent infections and frequently to death in early childhood

Question 29

IgG subclass: Properties

Answer 29

Question 30

What IgG subclass has the most complement fixing-properties

Answer 30

IgG3