immunology and serology exam 3: immunodeficiencies (catch up in previous lectures! )

Primary immunodeficiencies are what type of disease? When do they usually manifest?

• Inherited diseases that affect any aspect of immunity

• Usually manifest in childhood

What is a Secondary Immunodeficiency? What can they be caused by?

• Present at any age caused by environmental, metabolic disease, anatomical abnormalities, or infectious agents:

• AIDS, measles virus

• Malnutrition

• Sickle cell, cystic fibrosis, diabetes mellitus • Splenectomy

A child with recurrent infection in a single location is most likely to have an anatomic defect, rather than defect in immune system-

So, it may not be a systemic genetic immunodeficiency

With inherited immune deficiencies, Are often caused by recessive gene defects, most on the X chromosome, so _____ are more susceptible.

Males

Examples of inherited immune deficiencies (primary)

• Phagocytes

• Antibody production or isotype switching • B cells, T cell or NK cells

• Complement

• Cytokine production or receptors

• MHC I or II deficiency

Phagocyte deficiencies: Examples of neutrophil defects

• Reduced numbers (Neutropenia)

• Chronic granulomatous disease – defect in killing

• Defects in leukocyte adhesion

Neutropenia

Transient states of neutropenia, often only noted on a single measurement, and not lasting for more than two weeks, are common in children and not usually associated with clinical problems.

• Neutropenia in neonates might also be caused by exhaustion of bone marrow reserves and can be an important sign of severe generalized infection, such as septicemia.

• Drugs, toxins, etc can also contribute to transient neutropenias.

• Chronic neutropenias are defined as abnormally low absolute neutrophil counts lasting more than six months.

• Inherited, drugs, neutrophil specific autoimmune antibodies etc may be the cause

• Present primarily with bacterial infections, e.g. staphylococci, streptococci and gram

negative enteric bacteria, but in some cases increased fungal infections occur.

• Susceptibility to infection is dependent on severity of neutropeni

Chronic granulomatous disease (CGD)

Phagocytes have abnormal respiratory bursts, so patients have recurrent bacterial and fungal infections

• defects in NADPH oxidase

• May need corticosteroids to reduce inflammatory response

The three types of leukocytes adhesion deficiencies

• LAD I – CD18 mutation

• LAD II – CD15s mutation

• LAD III – FERMT3 mutation

LAD I is characterized by

High WBC count, delayed umbilical cord separation, defective wound healing, skin ulcers and recurrent bacterial infections

• CD18 deficieny

• Limited typically to bacterial infections, gingivitis, periodontitis, skin infections, and respiratory tract infections

  • Fungal infections unusual

Antibody deficiency diseases are usually what type of defects? and what are examples of clinical manifestations

Usually genetic defects

Clinical manifestations:

• Recurrent bacterial and/or viral infections

• Primarily due to encapsulated pyogenic bacteria (Steptococcus pneumonia, Hemophilus influenza type b)

• Viral infections are cleared normally, but protective immunity doesn’t develop

• Increased prevalence of other immunologic disorders

• Depending on severity and type, a paradoxic increase in risk of antibody mediated autoimmune disorders

• Lymphoid hypertrophy

• Allergic disorders, especially among patients with IgA deficiency

Antibody deficiency disease: Bruton’s X-linked agammaglobulinemia (XLA)

results in a loss of B cells. (think Bruton= no B)

•loss of protein kinase (Btk),that is expressed on PMN and B cells.

• B cell maturation halts at the pre-B cell stage

•Infection susceptibility:Encapsulated bacteria,enterovirus,helicobacter and related species

What is X linked hyper-IgM syndrome?

A disorder in which CD40L on activated T cells cannot engage CD40 on B cells (which are normal)

• No isotype switching occurs; only IgM is produced

• Infection susceptibility: encapsulated bacteria such as Cryptosporidium

• Selective IgA deficiency

• most common immunodeficiency

• Patients tend to have more sinopulmonary infections with encapsulated organisms and can have increased intermittent diarrhea, systemic infections (e.g. viral hepatitis, meningoencephalitis and septicemia)

  • some have increased IgE levels

  •often develop autoimmune diseases such as juvenile rheumatoid arthritis, SLE, insulin dependent diabetes, Sjögren’s syndrome

Severe combined immune deficiency (SCID)

Defects in T cells can also compromise B cells and their responses.

Examples of SCID causes:

Deficiencies in RAG-1/2

-lead to failed T and B cell responses due to a lack of TCR or BCR development.

-RAG 1 and 2 proteins are involved in the DNA rearrangements involved in forming variable regions of antibody H and L chains, as well as T cell receptor.

-No T cells, B cells, but have NK cells

SCID: T cell mutations in cytokine receptors

• Defects gamma chain of IL-2 receptor are the most common cause of SCID.

• B cells may be present but no T cells or NK cells

RAG 1 and 2 functions

Help in formation of variable regions

Mutations can result in a partial loss of RAG protein function (hypomorphic mutations), and that can include:

• Susceptibility to opportunistic infections.

• Persistence of non-infectious granulomas in skin, bones, lymph nodes, sinus, etc.

• Autoimmune blood cell cytopenia and disseminated CMV infection are common

Bare lymphocyte syndrome types I and II

lack of MHC II inhibits positive selection of CD4 T cells, but platelets still have proper CD8 T cells function

Conversely, lack of TAP proteins impedes peptide binding to MHC I, leading to a deficiency in CD8 T cells

Di George syndrome

thymic epithelium develops abnormally and T cells fail to develop properly. No CD4 or CD8 T cells, impaired B cell activation

• Attempts to correct using allogeneic hematopoeitic stem cell transplantation has not been very successful, most likely due to the problem being anatomic.

Chronic mucocutaneous candidiasis refers to a group of heterogenous disorders characterized by

persistent, debilitating and/or recurrent infections of the skin, nails, and mucus membranes, mainly with the fungal

pathogen Candida albicans (also can be associated with other infections such as HPV)

Complement deficiencies

Leads to impaired humoral immune function and the persistence of immune complexes

• Patients with mutations in the classical pathway are more susceptible to extracellular pathogens due to lack of clearance of opsonized bacteria

• Failures in the early complement components results in an inability to clear immune complexes.

• Complement components attach to soluble immune complexes and allow them to be transported, ingested and degraded by cell with complement receptors.

• Immune complexes deposit into tissues and activate phagocytes, causing inflammation and tissue damage.

• Failed membrane attack complex formation leads to impaired defense against Neisseria spp.

Secondary immunodeficiencies Examples

• AIDS

• Measles virus

• Malnutrition

• Sickle cell

• Cystic fibrosis

• Diabetes mellitus

• Splenectomy

1. Which of the
following diseases
results in a
secondary
immunodeficiency?

A. HIV infection
B. Bruton's tyrosine kinase deficiency
C. Leukocyte adhesion deficiency
D. Chronic granulomatous disease

A. HIV infection

Decreased CD3-positive
lymphocytes and a lack of
responsiveness to
phytohemagglutinin in the
circulation are typically
associated with:

A. inflammation.
B. transient hypogammaglobulinemia.
C. DiGeorge anomaly.
D. chronic granulomatous disease.

C. DiGeorge anomaly

. A 6-month-old baby has
suffered from recurrent
bacterial infections. Flow
cytometry results indicate a lack
of B cells but the presence of
normally functioning T cells.
Which is the most likely
diagnosis

A. Severe combined immunodeficiency
B. Common variable
hypogammaglobulinemia
C. DiGeorge syndrome
D. Bruton's tyrosine kinase deficiency

D. Bruton’s tyrosine kinase deficiency

. The accumulation of
immune complexes in renal
glomeruli or joints (lupus-
like syndromes) can be
caused by a deficiency in
the complement
component:
A. C5.
B. MASP.
C. properdin.
D. C2

D. C2

. Deficiency in
IgA often results
in increased
occurrence of
(pick all the
apply)

A. Allergies
B. Respiratory infections
C. Autoimmune diseases

allergies, respiratory infections, autoimmune diseases

Patients with
recombinase activating
gene 1 (RAG-1) or RAG-
2 deficiencies have
decreased numbers of:
A. monocytes.
B. granulocytes.
C. lymphocytes.
D. all the above.

C. lymphocytes

Delayed-type
hypersensitivity
skin tests are
used to screen
for:
A. humoral immunodeficiencies.
B. cell-mediated immunodeficiencies.
C. phagocyte immunodeficiencies.
D. complement deficiencies.

B. cell-mediated immunodeficiencies

A patient has a monoclonal serum band. Which of the following additional criteria would support a diagnosis of multiple myeloma?

Increased abnormal plasma cells in bone marrow or monoclonality of plasma cells

Which type of gene is required for cell growth and division but can cause malignant transformation when altered?

proto-oncogene

A patient’s immunofixation electrophoresis shows excessive amounts of free monoclonal light chains. These light chains are referred to as:

Bence-Jones proteins

Which of the following is characteristic of an acute graft-versus-host disease episode?

The reaction involves the skin, gastrointestinal (GI) tract, and liver.

In direct allorecognition, the recipient T cells bind and respond directly to foreign HLA proteins.

True

The most serious impairment of opsonization and antimicrobial defense is caused by a deficiency in complement component:

C3

A nitroblue tetrazolium test shows little color in cells observed under a microscope. What disease does this finding correlate with?

Chronic granulomatous disease (CGD) (think: blue = working WBCs)

Which of the following statements about severe combined immunodeficiency (SCID) is true?

It may be associated with a signal transduction defect.

Serum samples from day 1 and day 4 were collected from a patient showing signs of disease. The serum samples were assayed for IgG titer against a potential pathogen consistent with the patient’s clinical signs. The titers for the first sample was 16 while the second sample was 32.

Need a sample taken later as the two samples assayed may have been collected too close together.

Remember: 1:32 means a high concentration of antibodies

titer of 1:16 indicates active infection

The basic difference between a leukemia and lymphoma is the

migration patterns of cells

Suppose a mother and her child possess the following HLA haplotypes:

Mother:
A28  B17  Cw4  Dw3
A30  B21  Cw2  Dw10
Child:
A3  B8  Cw6  Dw7
A28  B17  Cw4  Dw3

Paternity testing was performed. Three potential fathers were HLA typed and found to contain the following haplotypes:

Father 1: 
A30  B21  Cw2  Dw10
A1  B2  Cw5  Dw9

Father 2:  
A3  B8  Cw6  Dw7
A8  B9  Cw1  Dw8

Father 3:
A3  B8  Cw5  Dw4
A2  B1  Cw6 Dw7

Which of the following statements is true?

The father may be either father 2 or 3

Which of the following diseases is characterized by skin involvement?

Sézary syndrome

transplantation patient suffers an organ rejection within hours after the procedure. What type of rejection occurred?

Hyperacute

Your otherwise healthy Caucasian patient has recurrent sinopulmonary infections and diarrhea. You find there is an isolated antibody deficiency.  This rather common immunodeficiency disorder is most likely to be

IgA

Decreased CD3-positive lymphocytes and a lack of responsiveness to phytohemagglutinin in the circulation are typically associated with

DiGeorge anomaly

If a patient suffers with an increased susceptibility to septicemias by Neisseria sp., but not other bacteria. Which of the following complement activities is most likely deficient in this patient?

Formation of membrane attack complex

Which of the following findings is a diagnostic criterion for monoclonal gammopathy of undetermined significance?

Plasma cell count lower than 10% of total cells in bone marrow

A 7-month-old boy is seen by a specialist because of hypocalcemia, viral pneumonia, a history significant for recurrent diarrhea, and oral candidiasis. An x-ray reveals the lack of a thymic shadow. A likely diagnosis for this boy is:

DiGeorge anomaly

A 9-month-old boy is suspected of having an immune deficiency because he had many recurrent infections with Streptococcus pneumoniae. Laboratory tests reveal a normal percentage of T cells and T-cell subsets but a lack of mature B cells and immunoglobulins. This boy most likely has:

X-linked agammaglobulinemia

Which is true of selective IgA deficiency?

Patients may develop an anti-IgA antibody

Decreased CD3-positive lymphocytes and a lack of responsiveness to phytohemagglutinin in the circulation are typically associated with:

Di George anomaly

In a patient who is exhibiting signs of graft-versus-host disease, which cell type is most likely responsible for the reaction?

T cells

A child suspected of having an inherited humoral immunodeficiency disease is given a diphtheria/tetanus vaccine. Two weeks after the immunization, his level of antibody to the specific antigens is measured. Which result is expected for this patient if he does have this deficiency?

No change in the level of specific antibody

True or false; In direct allorecognition, the recipient T cells bind and respond directly to foreign HLA proteins.

True

Which of the following findings is a diagnostic criterion for monoclonal gammopathy of undetermined significance?

Plasma cell count lower than 10% of total cells in bone marrow

In indirect allorecognition, the host’s T helper cells recognize foreign protein and uptake, process, and present it to recipient antigen-presenting cells (APCs). True or False?

False

A 6-month-old baby has suffered from recurrent bacterial infections. Flow cytometry results indicate a lack of B cells but the presence of normally functioning T cells. Which is the most likely diagnosis?

Bruton's tyrosine kinase deficiency (XLA)