Lesson 6

Question 1

Features of the HLA/MHC class I and class II

Answer 1

• MHC molecules are trans membrane proteins expressed on the cell surface
• The glycoproteins are coded by a cluster of genes called MHC: it is present in all vertebrates, in humas is called HLA (human leukocyte antigen)
• The genes are polygenic and polymorphic: there are many co-dominant alleles for each gene
• A few of the genetic polymorphisms are due to a single nucleotide polymorphism (SNP) while others involve hundred of base pairs
• Distinct alleles of class I and class II HLA genes have different frequency in the vary part of the world

Question 2

Which are the types of MHC molecules?

Answer 2

• Class I: show what’s happening inside the cell
• Class II: show what’s happening inside the cell
• Class III: it’s involved in the immune response
• Non-classical MHC: they are very similar from a genetic point of view, but they do not participate in the antigen presentation

Question 3

Features of HLA genes

Answer 3

polygenic
codominant
polymorphic

Question 4

Describe the general structure of a HLA class I molecule

Answer 4

only one big protein chain with 3 extracellular glomerular domain (α), a transmembrane domain and a very short tail in the cytoplasm.
There’s also a β2-microglobulin

Question 5

Describe the alfa chain of the HLA class I

Answer 5

The α chain is a highly polymorphic chain, between α1 and α2 domain there is a pocket in which small peptides (8-10 amino acids), or what’s inside, are shown on the cell surface. Normally they will show some cell proteins, if the cell is infected viral or bacterial protein will be located on the pocket.
The α chain bind to specific amino acids (anchor amino acids), usually the 2° and the 8°, which are specific. The bond between the peptide and the MHC class I is not covalent so these molecules can bind different type of peptides.
HLA I peptide complex is recognized specifically by the TCR expressed by the T lympocyte.

Question 6

HLA class 1: constitutive or inducible?

Answer 6

The expression of HLA class I molecules is constitutive in most in all cells with the exception of neuronal, endocrinal and some of muscle cells. can be induced and increased in response of some tissue factor for class II or citokynes (TNF and inferferon for example).

Question 7

Non-classical HLA class I molecules: list and general features

Answer 7

HLA E, HLA F: in gamma-delta lymphocytes, for glicosilated proteins or glicoproteins
HLA G: in the trofoblast, recognize NK cell
MIC-A, MIC-B: stress ligand, activate NK cells and gamma delta lymphocytes
HFE: responsible for hemochromatosis
Other non-classical molecules: the genes are outside the complex, involved in the immune response

Question 8

General structure of HLA class II

Answer 8

Class II molecules are constituted by 2 chains (α and β), a transmembrane domain and a short cytoplasmatic domain.
α chain is bigger than β

Question 9

Which is the role of class II trans activators?

Answer 9

they can induce the expression of more transcriptional factors that induce the expression of MHC class II also in different cells.
An example is CIITA.

Question 10

Where can we find HLA class II molecules?

Answer 10

These molecules can be constitutively expressed by dendritic cells, Langerhans cells, epithelial cells and macrophages.
During the infection there is the production of the interferon, especially interferon γ. The signalling from the interferon γ receptors (JAK-STAT pathway) can induce the expression of CIITA. In any kind of cells that have the interferon γ receptor, the CIITA can induce the expression of MHC class II molecules.

Question 11

Codominance of HLA class II molecules: Which scenarios can we have ?

Answer 11

• Cis-codominance: for each molecule we have 2 genes (α and β) from the father that can combine together, the same happens with the genes from the mothero. They’re forming the same molecule present on the parent.
• Trans-codominance: we can have the α chain from the father and the β chain from the mother or viceversa. This increases the potencial combination.

Question 12

Which are the consequences of disfunctioning HLA class II molecules?

Answer 12

Genetic defects on these genes lead to a serious immunodeficiency (nude lymphocyte syndrom): class II molecule is recognized by the T lymphocyte and is expressed on the thymic epithelial cells where the lymphocytes mature (class II molecules are important for the maturation of the lymphocytes).
If this molecule lacks the T cells cannot recognize the CD4, so they cannot mature and exit from the thymus. This population of T cells is necessary for the B cells activation and for the CIITA activation so these people have serious defect in the immune response.

Question 13

Which are the differences between HLA class I and class II structures?

Answer 13

Pocket: class I=8-10 aa, class II=13-20aa
Number of chain: class I=1 alfa, class II= 1 alfa+1beta
helper protein: class I=beta2-microglobulin, class II=none

Question 14

Which are two non-classical class II molecules?

Answer 14

DM and DO are made as the classical one (two chains) but they don’t form the groove: they aren’t exposed on the cell surface, they work as chaperonin to allowing the transport of the MHC class II molecule on the cell surface (they’re still participating to the antigen presentation process but remaining inside).

Question 15

Which are the genes in the HLA class III complex?

Answer 15

• Gene for hydroxylase: it’s and enzyme for steroid biosynthesis
• C4, C2 and B factor: belong to the complement system (they’re inside the HLA complex
• Lymphotoxin: a cytokine released by macrophages or contained in the granule of the neutrophil, important for the activation of cytotoxic T cells
• TNF: cytokine

Question 16

1- Which are the functions of class I and class II molecules?

Answer 16

Both class I and class II molecules present on the cell surface fragments of proteins either coded or endocyted by the cell. This peptide is a communication code that led to T cell activation

Question 17

2- What the polymorphism of HLA/MHC genes does?

Answer 17

encodes the molecules signalling out individuality, induce different kind of response to the same pathogen in different individuals and control the susceptibility to the immune response.