Which MHC class of molecules are present on the immune cells of the body?

MHC-II

Which body cells have no MHC markers?

Red blood cells

Which group of immune cells cannot “see” an antigen at all , unless it is sitting in an MHC-II molecule?

T cells – CD4+ type

How is an “HLA” related to the “MHC?”

Consider them the same – Technically, HLA is for humans

Which lymphocytes can attack things even if the targets have neither MHC-I nor MHC-II molecules on their surface?

Natural killer (NK) cells

What is the main function of CD4+ T-helper cells?

To stimulate antibody production by B-cells (& B cell maturation)

How do CD4+ T-helper cells get activated?

By encountering MHC-II molecules loaded with antigen on other immune system cells

(antigen-presenting cells)

There are actually two types of CD4+ T-cells – the helpers (which increase B cell antibody production)

and what other group?

Regulatory CD4+ T cells

(previously known as suppressor-inducer cells)

What does a regulatory T cell do?

Suppresses immune activation. They are important in regulating the development of autoimmunity

The overall impact of CD4+ T-cells on antibody production (by B cells) is _________?

Regulation

(up or down,

depending on which CD4+ cells are active)

If a cell is CD56+ and CD16+, what kind of T cell is it?

Natural killer

There are two populations of CD8+ T cells. What are they?

1. Cytotoxic

2. Regulatory

(modifying B cell antibody production)

Which class of T cells is most important in defending against viruses and cancer?

Cytotoxic CD8+

What two important classes of surface markers are on the surface of B cells?

Immunoglobulins

  &

MHC-II

What two events stimulate B cells to become plasma cells?

Interacting with CD4+ cells

  Or

Direct interaction with antigen

Which type of immunoglobulin is found in various body secretions?

IgA

Which type of immunoglobulin is secreted when the immune system begins its response to a new antigen?

IgM

What is special about the structure of IgM?

It’s huge

(Five immunoglobulins joined like a big snowflake – officially called a “pentamer”)

Which immunoglobulin is the main one, in the body’s antibody response?

IgG

Which antibody is secreted when the body sees an antigen it has fought in the past?

IgG

If the initial immune system response is to produce IgM, and the later response is IgG, how does that happen?

“Class switching”

(The B cell changes from IgM production to IgG production)

IgM is usually found as a pentamer. IgA, on the other hand, is usually found as what type of structure?

As a dimer (2 IgAs joined together)

  +

a secretory piece

(the secretory piece is added by the epithelial cells, during processing for secretion)

How is the structure of IgA different, when it is in the serum?

It is a monomer

What are the two areas of an immunoglobulin molecule called?

(created in the lab by partially digesting the protein)

Fab

&

Fc

There are also two regions of immunoglobulin molecules, which correspond to the two sections of the immunoglobulin. What are they?

The constant region

&

variable “antibody-binding” region

(the variable region is made up of both the light chain & part of the heavy chain)

Which part of the immunoglobulin is variable, with a huge number of possible shapes to bind antigen?

Fab region

(As in Fab fragments to bind things up)

(Ab = antigen-binding region)

Which part of the immunoglobulin activates complement, or sometimes other immune cells, to eliminate bound antigens?

Fc region

(c = cell or complement-binding area)

C also equals constant region

Which type of immunoglobulin has four different subtypes?

IgG

Which type of immunoglobulin both crosses the placenta and is also found in breast milk?

IgG

(IgA is also in breast milk, but it doesn’t cross the placenta)

Which portion of the immune system is referred to as the “humoral” system?

The B cell portion

Which portion of the immune system is called the “cellular” immune system?

The T cell portion

(even though plenty of other cells are also involved)

SCID refers to “severe combined immune deficiency.” Which sets of immune cells are often deficient in this “combined” disorder?

B & T cells

(sometimes also NK cells – various combinations are possible within the diagnosis “SCID”)

Why is SCID often missed in the neonatal period?

Lymphocyte counts are “abnormally” high during infancy, so their lymphocyte count may appear normal, and neonates are often not exposed to life-threatening infections that would reveal the faulty immune system

Why are more infants within the USA now being diagnosed with SCID very early?

Since 2008, a variety of states have added SCID to their newborn screening program (with good success in detecting SCID infants)

What is the lower limit for absolute lymphocyte count at birth?

2,500/mm³

Which infectious etiologies are SCID children at increased risk for?

All of them

By what age would you expect SCID patients to present, and how do they typically present?

By 3 months –

Typically with recurrent or persistent thrush, diarrhea, respiratory infections, & failure to thrive

What anatomic abnormality is classically seen on the chest X-ray of an infant with SCID?

No visible thymus

(missing “sail sign”)

What vaccinations should you not give to patients with SCID?

No live attenuated vaccines!

What is the most common way to inherit SCID?

X-linked

(47 % of US cases)

If SCID is not inherited as an X-linked disorder, it is usually inherited in what fashion?

Autosomal recessive

(variety of mechanisms)

(most common in Europe)

What is special about transfusing an SCID patient?

Blood must be irradiated to destroy the foreign WBCs

(leukocyte depletion is NOT sufficient)

If a SCID patient receives a blood transfusion that has not been irradiated, what is the problem?

The foreign T cells may initiate a graft-versus-host disease against the patient

The second most common cause of SCID, after X-linked, is what specific cause?

Autosomal recessive purine salvage problems

(about 20 %)

Which two enzyme problems lead to purine salvage SCID?

Adenosine deaminase (ADA)

(15 % of cases)

  &

Purine nucleoside phosphorylase (PNP)

(around 4 % of cases)

While we often hear about ADA deficiency as a cause of SCID, we don’t often hear about PNP. Why not?

It is less common

  &

Less severe

What other body system is often abnormal in SCID patients whose underlying problem is ADA deficiency?

Skeleton

(especially pelvic dysplasia & costochondral joint abnormalities)

Mnemonic: Think of a skeletal gal named “ADA” who “scids” and injures her axial skeleton!

How do SCID patients with PNP deficiency (purine nucleoside phosphorylase) present differently from ADA deficiency patients?

(3 ways it’s better)(2 ways it’s worse)

• Presents later

• Less severe

• No skeletal issues

• + Neurological problems

• + Autoimmune problems

How is SCID usually treated?

Bone marrow transplant

(supportive care, until BMT is arranged)

For ADA-deficiency SCID patients, what temporary treatment is available, until bone marrow transplant can be arranged?

Bovine ADA enzyme replacement

If your patient has normal platelets and RBCs, but almost no white cells, what is the diagnosis?

SCID –

due to “reticular dysgenesis”

Reticular dysgenesis SCID is fatal in infancy unless what treatment is completed?

Bone marrow transplant

The treatment of choice for all forms of SCID is _______________?

Bone marrow transplant

Which two unusual causes of pneumonia are common in SCID children?

PCP (due to P. jiroveci)

  &

viral interstitial pneumonia

(due to adenovirus, CMV, etc.)

Regardless of the underlying problem, SCID patients should all have what lab finding?

Low absolute lymphocyte count

In reticular dysgenesis , the lymphocytes & granulocytes are both missing. Which cell populations are normal?

Platelets & RBCs

If a vignette states that your patient is missing B & T cells, yet the number of natural killer cells (another type of lymphocyte) is normal, what gene is mutated?

RAG 1 or 2

(known as RAG 1 or 2 deficiency)

SCID resulting from mutations in RAG1 and RAG2 would lead to which lymphocyte populations being absent?

Partial inactivation of the RAG 1 or 2 genes results in what syndrome?

T cells and B cells

(due to inability to repair double-stranded breaks formed during rearrangement)

Omenn

Mnemonic: Think of it as “omit” syndrome –

part of the gene has been “omitted”

Omenn syndrome develops when genes important to what special immune cell process are altered?

The V (D) J rearrangement genes

(these genes are important to the big diversity of antibodies the immune system can form, and also the diversity of antigen-type receptors found on B & T cells)

Immune deficiency + skin problems, diarrhea, & hepatosplenomegaly = what SCID-related syndrome?

Omenn syndrome

Omenn syndrome consists of lymphopenia & what three major symptoms/signs?

1. Skin problems (especially exfoliative erythroderma)

2. Diarrhea

3. HSM

Some children are born without MHC-II molecules. What is the name for their disorder?

MHC class II deficiency syndrome

(sensible enough name!)

Patients with MHC class II deficiency are especially likely to get which kinds of infections?

Viral!

They are have significant risk for pyogenic bacterial infections and opportunistic infections, but much less than is seen in SCID

What is the ultimate treatment for MHC class II deficiency?

Bone marrow transplant is the treatment of choice – but it may or may not fully cure the disorder

Non-hematopoietic cells are still missing the MHC II marker, which can impair important cell-to-cell interactions

If a patient’s SCID disorder is not an X-linked disorder, it is very likely to be what type of inheritance pattern?

Autosomal recessive

(Example: ADA deficiency)

If a pediatric patient has chronically high IgM levels, he or she will likely have low levels of what other immunoglobulins?

IgG, IgA, IgE

(all immunoglobulin types that require class switching)

How is hyper-IgM syndrome inherited?

X-linked (more common)

  &

Autosomal recessive (very rarely)

Which has the better prognosis, X-linked or autosomal recessive hyper-IgM syndrome, and why?

• Autosomal recessive

• Second decade risk of malignancy much higher for X-linked (especially liver cancer)

What is the underlying problem with hyper-IgM syndrome ?

CD40 molecules are defective.

CD40 is needed for Ig class switching

(e.g., IgM → IgG)

If a patient has a defect in CD40 or CD40L, what immunodeficiency will this cause?

Hyper-IgM syndrome – a type of immunodeficiency

(due to inability of T cells to activate B cells)

What are hyper-IgM patients given to reduce the chance of infection occurring?

IVIG

(& TMP/SMX for PCP prophylaxis)

Why are hyper-IgM patients routinely given trimethoprim-sulfamethoxazole?

High risk for PCP

(also known as Pneumocystis jiroveci )

How is hyper-IgM syndrome treated?

Trick question – it depends:

• X-linked – bone

 marrow transplant

• Recessive – IVIG & TMP/SMX

Boys with X-linked hyper-IgM syndrome often have what type of related disorders?

Autoimmune

Do you expect any abnormalities on physical exam of a patient with hyper-IgM syndrome?

Hepatosplenomegaly

  &

Enlarged lymph nodes

An infant boy presents with recurrent otitis media in the first year of life . His older brother is having difficulty with OM and frequent sinus infections. He has large lymph nodes , and HSM. What test should you send?

Immunoglobulin studies

What is “ common variable” immuno-deficiency ?

A (heterogeneous) group of immune disorders with:

Low-level production of most Ig types & difficulty making specific antibodies

B cell numbers are sometimes alright in common variable immunodeficiency, so what is the problem with the Ig?

The B cells don’t turn into plasma cells very well

(so not much Ig is made)

(T cell abnormalities are also involved for many patients, but their role in the disorder is not fully understood)

Can common variable immunodeficiency patients have a normal total IgG?

Yes –

sometimes

(but still immunocompromised)

If the serum IgG level is sometimes normal, why are common variable patients at increased risk of infection?

High-quality antibodies specific to a particular antigen cannot be made in quantity

How is common variable immunodeficiency different from SCID?

 (2 points)

• B cells are present, they just don’t differentiate well

• T cells are present

Common variable immunodeficiency (CVID) patients have frequent infections in what three parts of the body, especially?

• Lungs

• Gut

• Sinuses

What gut problem often accompanies common variable immunodeficiency ?

Sprue-like malabsorption

(and diarrhea)

(Also due to Giardia!)

When nodules are biopsied in CVID patients, what is a common finding?

Non-caseating granuloma

In addition to a sprue-like illness, are common variable patients likely to have other autoimmune-type problems?

Yes –

Anemias & arthritides

How are common variable immunodeficiency patients managed, in terms of infection?

IVIG

&

antibiotics

(as needed)

Are males or females more often affected by common variable immunodeficiency?

Affects both genders equally

(multiple genetic mechanisms)

DiGeorge syndrome has a variety of immune system manifestations. It usually results from deletion of which chromosome area?

22q11

In addition to immune abnormalities, what else is expected in DiGeorge syndrome?

 (4 items)

Heart problems

Facial abnormalities

Hypoparathyroidism

Intellectual disability

Low calcium + immune abnormalities in an infant or young child = (consider) what diagnosis?

DiGeorge syndrome

What does “complete” DiGeorge syndrome refer to?

Complete absence of the thymus & parathyroid glands –

T cells are absent

B cells are normal

Just 1 % of DiGeorge syndrome patients have this form . . .

If normal B cells are present, but there are no T cells, what are the consequences (if any) for B cell function?

B cells generally will not produce much antibody without T cell stimulation

(except in the special case of “thymic-independent antigens”)

“Complete” DiGeorge syndrome will present identically to what other disorder?

SCID –

Despite the normal number of B cells

If complete DiGeorge syndrome patients are clinically the same as SCID patients, then what must you worry about with transfusions of blood?

Graft-versus-host disease

(transfusions must be irradiated)

What treatment is available for complete DiGeorge syndrome patients?

 (3 options)

Thymic transplant

Bone marrow transplant

(results unclear to date)

  &

IVIG

Immunologically speaking, how do “partial” DiGeorge children present?

• Normal B cell function

• Partial T cell deficiency

What is the usual course of partial DiGeorge syndrome?

Improves over time

(reason not clear)

Which is more common, complete or partial DiGeorge ?

Partial

(fortunately!)

What electrolyte abnormality is often seen with DiGeorge syndrome?

Hypocalcemia

Due to hypoparathyroidism

(the parathyroid glands ordinarily located on the thyroid tissue also fail to form normally)

Which cardiac anomalies are most often present in DiGeorge syndrome patients?

1. VSDs

2. Conotruncal abnormalities (things like tetralogy of Fallot, or transposition of the great vessels)

If DiGeorge patients have mainly T cell abnormalities, what sort of infection(s) are they most at risk for?

(3)

1. Fungi

2. Viruses

3. Opportunistic organisms, such as PCP

(P. jiroveci, the cause of PCP is now considered a protozoan)

Sinus & pulmonary infections are common in a variety of immune deficiencies. If the vignette also mentions an elevated α1-fetoprotein, what is the disorder?

Ataxia – telangiectasia

What is the underlying problem in ataxia-telangiectasia ?

Defective DNA strand repair, due to a mutation in the ATM gene

(there are several subtypes – some are unusually sensitive to radiation damage – important to know if ordering radiology evaluations!)

What is the main problem affecting daily life for ataxia-telangiectasia patients?

Neurological problems –

Especially cerebellar ataxia

How do children with ataxia-telangiectasia present?

Ataxia first – in early childhood

Immune deficiency

Telangiectasias later

The board gives you a photo item of an eye with telangiectasia on the bulbar conjunctiva (the conjunctiva over the sclera). What immune disorder are they probably showing you?

Ataxia-telangiectasia

How is the immune system affected in ataxia-telangiectasia?

 (2 main effects)

B & T cell counts are low & cell function is often not good

  &

Hypogammaglobulinemia (due to impaired class switching)

Is ataxia-telangiectasia commonly diagnosed in the first year of life?

No

A child more than one year old + ataxia + α 1-fetoprotein = what diagnosis?

Ataxia-telangiectasia

Long-term, what are the two most severe complication of ataxia telangiectasia?

High rate of malignancy, especially leukemia/lymphoma

  &

Severe pulmonary infection

Bloom syndrome is a consequence of what enzyme deficiency ?

BLM gene

(it codes for a helicase in the nuclear matrix of growing cells)

Bloom syndrome presents very similarly to what other DNA repair disorder?

Ataxia-telangiectasia

(the DNA repair defect is also very similar)

The main features of Bloom syndrome are ________?

(4)

1. Short stature with microcephaly

2. Telangiectasia (sun-sensitive ones)

3. Immune deficiency

4. Early cancer development (especially leukemia)

Nijmegen breakage syndrome is rare, but tested on exams. What unusual combination of neuro-related findings occurs in this immunodeficiency syndrome?

Microcephaly

  With

Normal IQ in early childhood

(it later declines)

Nijmegen breakage syndrome , along with the closely related Berlin breakage syndrome, is considered to be a variant genetic disorder of what other DNA repair disorder?

Ataxia-telangiectasia variants

What malignancy are Nijmegen syndrome children likely to develop?

Lymphoid malignancies

What is the underlying problem in Nijmegen (breakage) syndrome?

Double-stranded DNA breaks are not repaired

(due to a missing protein)

Immune issues (both cellular & humoral) + normal IQ + small head = what disorder?

Nijmegen syndrome

Small platelets, and a low platelet count, are highly suggestive of what immune system disorder?

Wiskott-Aldrich syndrome

What triad is the core of Wiskott-Aldrich symptomatology ?

• Eczema

• Thrombocytopenia