Immunodeficiency Diseases

Question 1

What do we mean by immunodeficiency?

• Infections that are…….
• O..
• U..
• Unusually …, … or not responding to … …
• F…

Answer 1

• Infections that are…….
• Opportunistic
• Unusual
• Unusually severe, protracted or not responding to standard therapy
• Frequent

Question 2

Immunodeficiency - difficulty in defining

Answer 2

• So there is no definitive definition…….
  
  • The diagnosis is largely descriptive
  • Infections more likely to be significant if……..
    
    • Infections are verified rather than simply reported
    • Organisms can be identified
    • End-organ damage has occurred

Question 3

Infections more likely to be significant if…. (3)

Answer 3

• Infections are verified rather than simply reported
• Organisms can be identified
• End-organ damage has occurred

Question 4

General classification of immunodeficiency

• … immunodeficiency
• … immunodeficiency …

Answer 4

• Secondary immunodeficiency
  
  • Immune defect is secondary to another disease process
  • Very common
  • Extremes of age
  • Malignancies (esp myeloma, lymphoma)
  • Metabolic eg diabetes
  • Drugs eg chemotherapy, steroids
  • Infection eg HIV
• Primary immunodeficiency syndrome (PID)
  
  • Immune defect is intrinsic to the immune system itself
  • Rare
  • Often genetic, but not always
  • Over 100 characterised PIDS
  • Mostly are fairly ‘new’ diseases
  • Fatal in pre-antibiotic era
  • Characterisation required developments in technology

Question 5

Secondary immunodeficiency

• Immune defect is secondary to another disease process
• Very …
• Extremes of …
• … (esp myeloma, lymphoma)
• … eg diabetes
• … eg chemotherapy, steroids
• … eg HIV

Answer 5

• Immune defect is secondary to another disease process
• Very common
• Extremes of age
• Malignancies (esp myeloma, lymphoma)
• Metabolic eg diabetes
• Drugs eg chemotherapy, steroids
• Infection eg HIV

Question 6

Primary immunodeficiency syndrome (PID)

• Immune defect is … to the immune system itself
• …
• Often …, but not always
• Over … characterised PIDS
• Mostly are fairly ‘…’ diseases
• … in pre-antibiotic era
• Characterisation required developments in …

Answer 6

• Immune defect is intrinsic to the immune system itself
• Rare
• Often genetic, but not always
• Over 100 characterised PIDS
• Mostly are fairly ‘new’ diseases
• Fatal in pre-antibiotic era
• Characterisation required developments in technology

Question 7

Immunological classification of immunodeficiency

Answer 7

Question 8

Immunological classification of immunodeficiency

Answer 8

Question 9

More notes on immunodeficiency……..

• CD… T cell defects affect B cells, as T cell help is need for B cell maturation
• This is particularly marked in …; less marked in …,
• Immunodeficiency syndromes affecting both antibody production and T cells are called … …
• In addition to infections, many immunodeficiency syndromes manifest with immune …: uncontrolled …, … diseases

Answer 9

• CD4 T cell defects affect B cells, as T cell help is need for B cell maturation
• This is particularly marked in infants; less marked in adults, who have already matured their B cells
• Immunodeficiency syndromes affecting both antibody production and T cells are called combined immunodeficiencies
• In addition to infections, many immunodeficiency syndromes manifest with immune dysregulation: uncontrolled inflammation, autoimmune diseases

Question 10

More notes on immunodeficiency……..

• CD4 T cell defects affect B cells, as T cell help is need for B cell …
• This is particularly marked in infants; less marked in adults, who have already … their B cells
• Immunodeficiency syndromes affecting both … production and T cells are called combined immunodeficiencies
• In addition to infections, many immunodeficiency syndromes manifest with immune dysregulation: … inflammation, autoimmune diseases

Answer 10

• CD4 T cell defects affect B cells, as T cell help is need for B cell maturation
• This is particularly marked in infants; less marked in adults, who have already matured their B cells
• Immunodeficiency syndromes affecting both antibody production and T cells are called combined immunodeficiencies
• In addition to infections, many immunodeficiency syndromes manifest with immune dysregulation: uncontrolled inflammation, autoimmune diseases

Question 12

Aging and immunity (‘immunosenscence’)

‘A combination of age-related changes in the immune system that result in greater … to infection and reduced response to …’

Answer 12

‘A combination of age-related changes in the immune system that result in greater susceptibility to infection and reduced response to vaccination’

Question 13

What is ‘immunosenscence’?

Answer 13

‘A combination of age-related changes in the immune system that result in greater susceptibility to infection and reduced response to vaccination’

Question 14

Some immunological aspects of immunosenescence

• Thymic …
• Telomere … in stem cells reduces both quality and quantity of leucocyte output
• Reduced T and B cell receptor …
• Reduced … responses
• Reduced neutrophil function
• Reduced self-tolerance; inflammation switches from protection to damage
• Expansion of T cell pool responding to cytomegalovirus (current research focus)

Answer 14

• Thymic involution
• Telomere shortening in stem cells reduces both quality and quantity of leucocyte output
• Reduced T and B cell receptor diversity
• Reduced vaccine responses
• Reduced neutrophil function
• Reduced self-tolerance; inflammation switches from protection to damage
• Expansion of T cell pool responding to cytomegalovirus (current research focus)

Question 15

Some immunological aspects of immunosenescence

• Thymic involution
• Telomere shortening in stem cells reduces both quality and quantity of leucocyte output
• Reduced T and B cell receptor diversity
• Reduced vaccine responses
• Reduced … function
• Reduced …-…; inflammation switches from protection to damage
• Expansion of T cell pool responding to … (current research focus)

Answer 15

• Thymic involution
• Telomere shortening in stem cells reduces both quality and quantity of leucocyte output
• Reduced T and B cell receptor diversity
• Reduced vaccine responses
• Reduced neutrophil function
• Reduced self-tolerance; inflammation switches from protection to damage
• Expansion of T cell pool responding to cytomegalovirus (current research focus)

Question 16

Elderly clearly more susceptible to infection, but immunity itself is not the only factor:

• Reduced …
• n…
• … healing
• Co-… (COPD, CCF, DM, cancer, depression etc)
• Reduced … reserve
• All of these increase … of infection AND risk of poor … from infection
• See VZV immunisation slides: clear that older people can make a response to a specifically tailored immune booster

Answer 16

• Reduced mobility
• Nutrition
• Wound healing
• Co-morbidities (COPD, CCF, DM, cancer, depression etc)
• Reduced physiological reserve
• All of these increase risk of infection AND risk of poor outcome from infection
• See VZV immunisation slides: clear that older people can make a response to a specifically tailored immune booster

Question 17

Predominantly antibody deficiency

• Low Ig…; other isotypes may be affected, but low IgA/ M with normal … is rarely significant
• Manifests with recurrent … infections of the upper and lower respiratory tract
• Sometimes … infections in addition
• Infections typically respond to anti-…, but response may be sub-optimal and long courses required
• If untreated, leads to irreversible lung damage (…)

Answer 17

• Low IgG; other isotypes may be affected, but low IgA/ M with normal IgG is rarely significant
• Manifests with recurrent pyogenic infections of the upper and lower respiratory tract
• Sometimes gut infections in addition
• Infections typically respond to anti-microbials, but response may be sub-optimal and long courses required
• If untreated, leads to irreversible lung damage (bronchiectasis)

Question 18

Predominantly antibody deficiency

• Low IgG; other isotypes may be affected, but low IgA/ M with normal IgG is rarely significant
• Manifests with … pyogenic infections of the …and … … tract
• Sometimes gut infections in addition
• Infections typically respond to anti-microbials, but response may be …-optimal and … courses required
• If untreated, leads to … lung damage (bronchiectasis)

Answer 18

• Low IgG; other isotypes may be affected, but low IgA/ M with normal IgG is rarely significant
• Manifests with recurrent pyogenic infections of the upper and lower respiratory tract
• Sometimes gut infections in addition
• Infections typically respond to anti-microbials, but response may be sub-optimal and long courses required
• If untreated, leads to irreversible lung damage (bronchiectasis)

Question 19

Some causes of antibody deficiency

• Physiological
  
  • Transient … of infancy
• Secondary
  
  • Ig… loss:
    
    • Renal: .. syndrome
    • Skin: extensive ..
  • Impaired production:
    
    • Immunosuppressive drugs
• Primary
  
  • X-Linked agammaglobulinemia
  • X-Linked hyper-Ig… syndrome
  • (Common variable immunodeficiency – module 302)
  • Many others that are beyond scope

Answer 19

• Physiological
  
  • Transient hypogammaglobulinemia of infancy
• Secondary
  
  • IgG loss:
    
    • Renal: nephrotic syndrome
    • Skin: extensive burns
  • Impaired production:
    
    • Immunosuppressive drugs
• Primary
  
  • X-Linked agammaglobulinemia
  • X-Linked hyper-IgM syndrome
  • (Common variable immunodeficiency – module 302)
  • Many others that are beyond scope

Question 20

What is shown here?

Answer 20

Irreversible lung damage (bronchiectasis) as a result of untreated predominantly antibody deficiency

Question 21

What is shown here?

Answer 21

Irreversible lung damage (bronchiectasis) as a result of untreated predominantly antibody deficiency

Question 22

Secondary causes of antibody deficiency:

• IgG loss:
  
  • Renal: … syndrome
  • Skin: extensive …
• Impaired production:
  
  • … drugs

Answer 22

• IgG loss:
  
  • Renal: nephrotic syndrome
  • Skin: extensive burns
• Impaired production:
  
  • Immunosuppressive drugs

Question 23

Primary causes of antibody deficiency

• X-Linked …
• X-Linked hyper-… syndrome
• (Common variable immunodeficiency – module 302)
• Many others that are beyond scope

Answer 23

• X-Linked agammaglobulinemia
• X-Linked hyper-IgM syndrome
• (Common variable immunodeficiency – module 302)
• Many others that are beyond scope

Question 24

Maturation of antibody production

• In healthy infants there is normally a period of relative antibody deficiency around 6 months known as ‘transient … of infancy; this is a physiological state but can be correlated with increased …
• Infants with antibody deficiency usually present after 3-6 months; up until this time they are protected by … IgG antibody

Answer 24

• In healthy infants there is normally a period of relative antibody deficiency around 6 months known as ‘transient hypogammaglobulinemia of infancy; this is a physiological state but can be correlated with increased infections
• Infants with antibody deficiency usually present after 3-6 months; up until this time they are protected by maternal IgG antibody

Question 25

Maturation of antibody production

• In healthy infants there is normally a period of relative antibody deficiency around 6 months known as ‘… hypogammaglobulinemia of infancy; this is a … state but can be correlated with increased infections
• Infants with antibody deficiency usually present after …-… months; up until this time they are protected by maternal IgG antibody

Answer 25

• In healthy infants there is normally a period of relative antibody deficiency around 6 months known as ‘transient hypogammaglobulinemia of infancy; this is a physiological state but can be correlated with increased infections
• Infants with antibody deficiency usually present after 3-6 months; up until this time they are protected by maternal IgG antibody

Question 26

XLA – a prototype antibody deficiency syndrome

• Signalling via Bruton’s tyrosine kinase (btk) required for signal … at pro-… stage
• … arrest occurs if absent: no … chain rearrangement, no B cells leave marrow, no immunoglobulin production
• Disease is called …-linked agammaglobulinaemia (XLA); also known as Bruton’s disease, Btk deficiency or Bruton’s XLA

Answer 26

• Signalling via Bruton’s tyrosine kinase (btk) required for signal transduction at pro-B stage
• Maturation arrest occurs if absent: no heavy chain rearrangement, no B cells leave marrow, no immunoglobulin production
• Disease is called X-linked agammaglobulinaemia (XLA); also known as Bruton’s disease, Btk deficiency or Bruton’s XLA

Question 27

XLA – a prototype antibody deficiency syndrome

• Signalling via Bruton’s … kinase (btk) required for … transduction at pro-B stage
• Maturation arrest occurs if absent: no heavy chain rearrangement, no B cells leave …, no … production
• Disease is called X-linked agammaglobulinaemia (XLA); also known as Bruton’s disease, Btk deficiency or Bruton’s XLA

Answer 27

• Signalling via Bruton’s tyrosine kinase (btk) required for signal transduction at pro-B stage
• Maturation arrest occurs if absent: no heavy chain rearrangement, no B cells leave marrow, no immunoglobulin production
• Disease is called X-linked agammaglobulinaemia (XLA); also known as Bruton’s disease, Btk deficiency or Bruton’s XLA

Question 28

X-Linked hyper IgM syndrome (CD40L deficiency)

• Failure of B cell … from primary to secondary
• Low IgG & IgA, raised (or normal) Ig…
• Recurrent … infections
• Presents age 3-6 months
• The immunological … actually resides on the T cell
  
  • CD40 ligand (also known as CD154)
  • Interaction with CD40 on B cells required for affinity maturation

Answer 28

• Failure of B cell maturation from primary to secondary
• Low IgG & IgA, raised (or normal) IgM
• Recurrent bacterial infections
• Presents age 3-6 months
• The immunological lesion actually resides on the T cell
  
  • CD40 ligand (also known as CD154)
  • Interaction with CD40 on B cells required for affinity maturation

Question 29

X-Linked hyper IgM syndrome (CD40L deficiency)

• Failure of B cell maturation from … to …
• Low Ig… & Ig…, raised (or normal) IgM
• Recurrent bacterial infections
• Presents age ..-.. months
• The immunological lesion actually resides on the T cell
  
  • CD40 ligand (also known as CD154)
  • Interaction with CD40 on B cells required for … maturation

Answer 29

• Failure of B cell maturation from primary to secondary
• Low IgG & IgA, raised (or normal) IgM
• Recurrent bacterial infections
• Presents age 3-6 months
• The immunological lesion actually resides on the T cell
  
  • CD40 ligand (also known as CD154)
  • Interaction with CD40 on B cells required for affinity maturation

Question 30

Treating antibody deficiency

• Early recognition before … damage occurs
• Aggressive treatment of intercurrent …
• Replace …
• Long-term suppressive anti-…

Answer 30

• Early recognition before lung damage occurs
• Aggressive treatment of intercurrent infections
• Replace immunoglobulin
• Long-term suppressive anti-microbials

Question 31

X-Linked Hyper-IgM syndrome

Answer 31

Question 32

Cellular immunodeficiency

• Poor terminology; used to mean CD4 T cell deficiency
• When …, antibodies will also be affected (combined immunodeficiency)
• Manifests particularly with:
  
  • … infection
  • … infection
  • … infection
  • … infection
• Classic secondary cause is … infection

Answer 32

• Poor terminology; used to mean CD4 T cell deficiency
• When congenital, antibodies will also be affected (combined immunodeficiency)
• Manifests particularly with:
  
  • Opportunistic infection
  • Viral infection
  • Fungal infection
  • Mycobacterial infection
• Classic secondary cause is HIV infection

Question 33

Cellular immunodeficiency

• Poor terminology; used to mean CD4 T cell deficiency
• When congenital, antibodies will also be affected (… immunodeficiency)
• Manifests particularly with:
  
  • … infection
  • Viral infection
  • … infection
  • Mycobacterial infection
• Classic … cause is HIV infection

Answer 33

• Poor terminology; used to mean CD4 T cell deficiency
• When congenital, antibodies will also be affected (combined immunodeficiency)
• Manifests particularly with:
  
  • Opportunistic infection
  • Viral infection
  • Fungal infection
  • Mycobacterial infection
• Classic secondary cause is HIV infection

Question 34

Some conditions seen in cellular immunodeficiency, particularly advanced HIV

Answer 34

• Top left hand - candida oesophagitis
• Right hand - Cytomegalovirus retinitis
• Bottom left - Kapsosi’s sarcoma (malignancy) - driven by Human herpes virus infection
• Middle - pneumocystis carinii pneumonia (bilateral pneumonitis)
• Bottom right - compression of brain tissue - cerebral toxoplasmosis

Question 35

Severe combined immunodeficiency

• …, life-threatening … immunodeficiency
• Absent … cells
• … cells may be present, but are non-functional
• All basically present in a similar fashion
  
  • Usually soon after …
  • … (graft versus host - maternal lymphocyte engraftment)
  • Failure to thrive
  • Chronic diarrhoea
  • Infections, especially opportunistic
    
    • Bacterial
    • Mycobacterial (esp BCG)
    • Viral (esp CMV, EBV)
    • Fungal (PCP, oral thrush)

Answer 35

• Rare, life-threatening primary immunodeficiency
• Absent T cells
• B cells may be present, but are non-functional
• All basically present in a similar fashion
  
  • Usually soon after birth
  • Rash (graft versus host - maternal lymphocyte engraftment)
  • Failure to thrive
  • Chronic diarrhoea
  • Infections, especially opportunistic
    
    • Bacterial
    • Mycobacterial (esp BCG)
    • Viral (esp CMV, EBV)
    • Fungal (PCP, oral thrush)

Question 36

Severe combined immunodeficiency

• Rare, …-… primary immunodeficiency
• Absent T cells
• B cells may be present, but are …-…
• All basically present in a similar fashion
  
  • Usually soon after birth
  • Rash (graft versus host - maternal lymphocyte engraftment)
  • Failure to …
  • Chronic …
  • Infections, especially …
    
    • Bacterial
    • … (esp BCG)
    • … (esp CMV, EBV)
    • … (PCP, oral thrush)

Answer 36

• Rare, life-threatening primary immunodeficiency
• Absent T cells
• B cells may be present, but are non-functional
• All basically present in a similar fashion
  
  • Usually soon after birth
  • Rash (graft versus host - maternal lymphocyte engraftment)
  • Failure to thrive
  • Chronic diarrhoea
  • Infections, especially opportunistic
    
    • Bacterial
    • Mycobacterial (esp BCG)
    • Viral (esp CMV, EBV)
    • Fungal (PCP, oral thrush)

Question 37

Severe combined immunodeficiency (SCID)

• Variety of molecular causes, only three considered this year:
  
  • … …. chain deficiency
  • JAK… deficiency
  • RAG…/… deficiency

Answer 37

• Variety of molecular causes, only three considered this year:
  
  • Common gamma chain deficiency
  • JAK3 deficiency
  • RAG1/2 deficiency

Question 38

Severe combined immunodeficiency (SCID)

• Variety of molecular causes, only three considered this year:
  
  • Common gamma chain deficiency
  • … deficiency
  • … deficiency

Answer 38

• Variety of molecular causes, only three considered this year:
  
  • Common gamma chain deficiency
  • JAK3 deficiency
  • RAG1/2 deficiency

Question 39

Common gamma chain deficiency and JAK3 deficiency

• Common gamma-chain deficiency
  
  • …-linked SCID
  • Common gamma chain forms part of membrane receptor for several …, some of which are required for … cell maturation
  • Absent …cells
  • … cells present but non-functional
• JAK-3 deficiency deficiency
  
  • Autosomal … SCID
  • JAK-3 is downstream of common gamma chain; deficiency likewise prevents signalling
  • Immunologically … to gamma chain deficiency

Answer 39

• Common gamma-chain deficiency
  
  • X-linked SCID
  • Common gamma chain forms part of membrane receptor for several cytokines, some of which are required for T cell maturation
  • Absent T cells
  • B cells present but non-functional
• JAK-3 deficiency deficiency
  
  • Autosomal recessive SCID
  • JAK-3 is downstream of common gamma chain; deficiency likewise prevents signalling
  • Immunologically identical to gamma chain deficiency

Question 40

Common gamma chain deficiency and JAK3 deficiency

• Common gamma-chain deficiency
  
  • X-linked …
  • Common gamma chain forms part of membrane receptor for several cytokines, some of which are required for T cell …
  • Absent T cells
  • B cells present but non-…
• JAK-3 deficiency …
  
  • Autosomal recessive …
  • JAK-3 is downstream of common gamma chain; deficiency likewise prevents signalling
  • Immunologically identical to gamma chain deficiency

Answer 40

• Common gamma-chain deficiency
  
  • X-linked SCID
  • Common gamma chain forms part of membrane receptor for several cytokines, some of which are required for T cell maturation
  • Absent T cells
  • B cells present but non-functional
• JAK-3 deficiency
  
  • Autosomal recessive SCID
  • JAK-3 is downstream of common gamma chain; deficiency likewise prevents signalling
  • Immunologically identical to gamma chain deficiency

Question 41

RAG 1&2 deficiency

• An autosomal … form of SCID
• RAG 1/2 required for … … events between V(D)J gene segments
• No RAG1/2 means no … and … cell receptors

Answer 41

• An autosomal recessive form of SCID
• RAG 1/2 required for somatic recombination events between V(D)J gene segments
• No RAG1/2 means no T and B cell receptors

Question 42

SCID therapy

• What is no longer used?
• Now:
  • … … transplant
  • .. … harvested from …-matched donor:
  • Given to recipient by …
  • Engraft in … …
  • … of T and B cells

Answer 42

• Treatable - bubbles no longer used
• Stem cell transplant
• Stem cells harvested from HLA-matched donor:
• Given to recipient by infusion
• Engraft in bone marrow
• RECONSTITUTION of T and B cells

Question 43

Another combined immunodeficiency syndrome: DiGeorge syndrome

• Failure migration 3th/ 4th … arches
• Full phenotype:
  
  • Absent … (low calcium, tetany)
  • … palate
  • … heart defects
  • … aplasia (low T cell numbers, immunodeficiency)
• Most patients have microdeletions chromosome 22
• Variable presentation
  
  • Huge spectrum of immunodeficiency from mild-SCID-like
  • Autoimmunity is also common
  • Patients with 22q11 microdeletions may have none of the above, all of the above and anything inbetween

Answer 43

• Failure migration 3th/ 4th branchial arches
• Full phenotype:
  
  • Absent parathyroids (low calcium, tetany)
  • Cleft palate
  • Congenital heart defects
  • Thymic aplasia (low T cell numbers, immunodeficiency)
• Most patients have microdeletions chromosome 22
• Variable presentation
  
  • Huge spectrum of immunodeficiency from mild-SCID-like
  • Autoimmunity is also common
  • Patients with 22q11 microdeletions may have none of the above, all of the above and anything inbetween

Question 44

Another combined immunodeficiency syndrome: DiGeorge syndrome

• Failure migration …th/..th branchial arches
• Full phenotype:
  
  • Absent parathyroids (low calcium, t…)
  • Cleft palate
  • Congenital heart defects
  • Thymic aplasia (low … cell numbers, immunodeficiency)
• Most patients have microdeletions chromosome …
• … presentation
  
  • Huge spectrum of immunodeficiency from mild-…-like
  • … is also common
  • Patients with … microdeletions may have none of the above, all of the above and anything inbetween

Answer 44

• Failure migration 3th/ 4th branchial arches
• Full phenotype:
  
  • Absent parathyroids (low calcium, tetany)
  • Cleft palate
  • Congenital heart defects
  • Thymic aplasia (low T cell numbers, immunodeficiency)
• Most patients have microdeletions chromosome 22
• Variable presentation
  
  • Huge spectrum of immunodeficiency from mild-SCID-like
  • Autoimmunity is also common
  • Patients with 22q11 microdeletions may have none of the above, all of the above and anything inbetween

Question 45

Terminal complement deficiency

• Deficiency of terminal complement components …-… leads to specific susceptibility to … Species
• Otherwise immunologically robust
• Diagnose by functional complement … (speak to your immunology laboratory)

Answer 45

• Deficiency of terminal complement components C5-C9 leads to specific susceptibility to Neisseria Species
• Otherwise immunologically robust
• Diagnose by functional complement assays (speak to your immunology laboratory)

Question 46

Terminal complement deficiency

• Deficiency of terminal complement components C5-C9 leads to specific susceptibility to … Species
• Otherwise immunologically robust
• Diagnose by functional … assays (speak to your immunology laboratory)

Answer 46

• Deficiency of terminal complement components C5-C9 leads to specific susceptibility to Neisseria Species
• Otherwise immunologically robust
• Diagnose by functional complement assays (speak to your immunology laboratory)