Lecture 20: Immune Deficiencies Flashcards Preview

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Flashcards in Lecture 20: Immune Deficiencies Deck (30):
1

The infections associated with immunodeficiences have what typical features

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

2

What are Primary imune deficiences (PIDs)

  • 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

3

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

25-30 days 

4

What are the warning signs of Immunodefieciency disorder 

  • 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 

5

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

  • B cells 
  • T cells 
  • NK cells 

6

X-linked Agammaglobulinemia 

  • 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 

7

Autosomal recessive Agammaglobulinemia 

8

Common Variable Immune Deficiency

  • 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 
  •  

9

IgA deficiency 

  • 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 

10

Hyper IgM syndromes (HIGM)

  • 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 

11

Isolated IgG subclass Deficiency 

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

12

Transient Hypogammaglobulinemia of Infancy

  • 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

13

Wiskott-Aldrich Syndrome

  • 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 

14

Severe Combined Immune Deficiency (SCID) 

  • 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 

15

Defects in T-Cell Function 

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23

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

  • 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

24

Adenosine Deaminase Deficiency (ADA) 

  • 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-

25

Deficiency of Jak3

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

26

DiGeorge Syndrome (DGS)

  • 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 

27

MHC Class I Deficiency

  • Caused by inability of TAP1 molecules to transfer peptides to ER
  • CD8cells are deficient
    • This leads to recurring viral infections 
  • CD4 Are normal 
    • normal Ab production 
  • Normal DTH (delayed type hypersensitivity) 

28

Bare Lymphocyte Syndrome 

  • 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 CD4T cells
  • Variable hypogammaglobulinaemia (mainly IgA and IgG2) 
  • Leas to recurrent infections and frequently to death in early childhood 

29

IgG subclass: Properties 

30

What IgG subclass has the most complement fixing-properties 

IgG3