PLASMA PROTEINS AND IMMUNOGLOBULINS

OUTLINE
PLASMA ALBUMIN HAPTOGLOBULIN TRANSFERRIN

FERRITIN
CERULOPLASMIN IMMUNOGLOBULINS

PLASMA PROTEINS & IMMUNOGLOBULINS

PLASMA consists of water, electrolytes, metabolites, nutrients, proteins, hormones total CHON in plasma: 7-7.5 g/dL most common method of analyzing plasma CHON: electrophoresis

STARLING FORCES
9 25 1 25 1 ARTERIAL END: BHP- 37mmHg IFHP-1 mmHg BOP- 25 mmHg 11 17 37 VENOUS END:

BHP- 17mmHg
IFHP-1 mmHg BOP- 25 mmHg

PLASMA CHONs.
are mostly synthesized in the liver generally synthesized on membrane-bound polyribosomes are mostly glycoproteins

many exhibit polymorphism

each has a characteristic half-life in the circulation levels may increase during acute inflammatory

states or secondary to certain types of tissue damage

ALBUMIN

Albumin is the major CHON in plasma

60% of plasma CHON produced in the liver comprises about half of the blood serum protein synthesized in the liver as preproalbumin which

has an N-terminal peptide that is removed before the nascent protein is released from RER proalbumin cleaved in the Golgi vesicles to produce the secreted albumin

Functions of Albumin
Maintains oncotic pressure Transports thyroid hormones Transports other hormones, particularly fat soluble ones Transports fatty acids to the liver Transports unconjugated bilirubin Transports many drugs and serum albumin levels can affect the half-life of drugs Competitively binds calcium Buffers pH

Haptoglobin
abbreviated as Hp in blood plasma: binds free Hb released from

erythrocytes with high affinity and thereby inhibits its oxidative activity haptoglobin-hemoglobin complex removed by the reticuloendothelial system Clinical use
used to screen for and monitor intravascular hemolytic anemia In intravascular hemolysis: free hemoglobin released into

circulation haptoglobin binds the Hbdecline in Hp levels in extravascular hemolysis: the RES phagocytoses the erythrocytes and hemoglobin is not released into circulation normal haptoglobin levels

Haptoglobin
FUNCTIONS
-bind

free plasma hemoglobin which allows degradative enzymes to gain access to the hemoglobin -prevents loss of iron through the kidneys -protects the kidneys from damage by hemoglobin -acute phase reactant: levels increased in inflammatory state

Transferrin

Transferrin
blood plasma protein for iron delivery glycoprotein that binds iron very tightly but reversibly iron bound to transferrin is less than 0.1% (4 mg) of the total body iron, it is the most important iron

pool, with the highest rate of turnover (25 mg/24 h) has a molecular weight of ~76 kD contains 2 specific high-affinity Fe(III) binding sites

Transferrin
main source is the liver

main role: deliver iron from absorption centres in the

duodenum to all tissues decreases in inflammation CLINICAL SIGNIFICANCE: increased in patients with iron deficiency anemia decreased in iron overload diseases and protein malnutrition

FERRITIN

FERRITIN

globular protein complex consisting of 24 protein

subunits primary intracellular iron-storage protein in both prokaryotes and eukaryotes keeps iron in a soluble and non-toxic form Ferritin that is not combined with iron is called apoferritin

FERRITIN
serves to transport iron to areas that it is required presence of iron itself is a major trigger for the production

of ferritin apoferritin binds to free ferrous iron and stores it in the ferric state as ferritin accumulates within cells of the RES, protein aggregates are formed as hemosiderin
CLINICAL SIGNIFICANCE
under steady state conditions, serum ferritin level

correlates with total body iron stores

Ceruloplasmin

Blue in color due to high copper content

Ceruloplasmin

Kayser-Fleisher ring

PLASMA IMMUNOGLOBULINS
2 major components

1. B lymphocytes -mainly bone marrow derived -synthesis of circulating humoral antibodies called immunoglobulins 2. T lymphocytes -thymic origin -cell mediated immunologic processes

GENERAL FUNCTIONS OF IMMUNOGLOBULINS

A. Antigen binding Ig bind specifically to one or a few closely related antigens primary function of antibodies and can result in protection of the host valency of antibody refers to the number of antigenic determinants that an individual antibody molecule can bind

GENERAL FUNCTIONS OF IMMUNOGLOBULINS

B. Effector Functions

1. Fixation of complement
results in lysis of cells and release of biologically active

molecules

2. Binding to various cell types

Ie. phagocytic cells, lymphocytes, platelets, mast cells,

and basophils some immunoglobulins also bind to receptors on placental trophoblasts, which results in transfer of the Ig across the placentatransferred maternal antibodies provide immunity to the fetus and newborn

BASIC STRUCTURE OF IMMUNOGLOBULINS

A. Heavy and Light Chains All Ig have a 4 chain structure as their basic unit composed of two identical light chains (23kD) and two identical heavy chains (5070kD)

BASIC STRUCTURE OF IMMUNOGLOBULINS

B. Disulfide bonds 1. Inter-chain disulfide bonds
heavy and light chains and the 2 heavy chains are held

together by inter-chain disulfide bonds and by noncovalent interactions No. of inter-chain disulfide bonds varies among different immunoglobulin molecules

2. Intra-chain disulfide bonds

Within each of the polypeptide chains there are also

intra-chain disulfide bonds.

BASIC STRUCTURE OF IMMUNOGLOBULINS

BASIC STRUCTURE OF IMMUNOGLOBULINS

C. Variable (V) and Constant (C) Regions both the heavy and light chain could be divided into 2 regions based on variability in the amino acid sequences. These are the: 1. Light Chain - VL (110 amino acids) and CL (110 amino acids) 2. Heavy Chain - VH (110 amino acids) and CH (330-440 amino acids)

BASIC STRUCTURE OF IMMUNOGLOBULINS

D. Hinge Region region at which the arms of

the antibody molecule forms a Y called the hinge region because there is some flexibility in the molecule at this point

IMMUNOGLOBULIN FRAGMENTS: STRUCTURE/FUNCTION RELATIONSHIPS

produced by proteolytic digestion

A. Fab
antigen binding or Fab fragments contained the antigen binding sites of the

antibody each Fab fragment is monovalent whereas the original molecule was divalent combining site of the antibody is created by both VH and VL different combinations of a VH and VL result in antibodies that can bind a different antigenic determinants.

IMMUNOGLOBULIN FRAGMENTS: STRUCTURE/FUNCTION RELATIONSHIPS

B. Fc Fc =easily crystallized mediates effector functions Ig

HUMAN IMMUNOGLOBULIN CLASSES

HUMAN IMMUNOGLOBULIN CLASSES

Immunoglobulin classes

-divided into 5 different classes, based on differences in the amino acid sequences in the constant region of the heavy chains
All Ig within a given class will have very similar heavy chain

constant regions. These differences can be detected by sequence studies or more commonly by serological means (i.e. by the use of antibodies directed to these differences).

1. IgG - Gamma heavy chains 2. IgM - Mu heavy chains 3. IgA - Alpha heavy chains 4. IgD - Delta heavy chains 5. IgE - Epsilon heavy chains

STRUCTURE AND SOME PROPERTIES OF IG CLASSES

A. IgG 1. Structure
monomers subclasses differ in the number of disulfide bonds and length of

the hinge region

2. Properties most versatile immunoglobulin because it is capable of carrying out all of the functions of immunoglobulin molecules.
a) IgG is the major Ig in serum - 75% of serum Ig is IgG b) IgG is the major Ig in extra vascular spaces
c) Placental transfer

only class of Ig that crosses the placenta

STRUCTURE AND SOME PROPERTIES OF IG CLASSES

B. IgM
Structure normally exists as a pentamer but it can also exist as a monomer the pentameric form all heavy chains are identical and all light chains are identical

Properties a) 3rd most common serum Ig. b) 1st to be made by the fetus and 1st Ig to be made by a virgin B cells when it is stimulated by antigen. c) good complement fixing Ig very efficient in leading to the lysis of microorganisms. d) As a consequence of its structure, IgM is also a good agglutinating Ig.

STRUCTURE AND SOME PROPERTIES OF IG CLASSES

C. IgA 1. Structure Serum IgA is a monomer but IgA found in secretions is a dimer
2. Properties a) IgA is the 2nd most common serum Ig. b) IgA is the major class of Ig in secretions tears, saliva, colostrum, mucus important in local (mucosal) immunity.

STRUCTURE AND SOME PROPERTIES OF IG CLASSES

D. IgD

1. Structure exists only as a monomer. 2. Properties a) found in low levels in serum; its role in serum uncertain b) primarily found on B cell surfaces where it functions as a receptor for antigen

STRUCTURE AND SOME PROPERTIES OF IG CLASSES

E. IgE 1. Structure exists as a monomer 2. Properties a) IgE is the least common serum Ig since it binds very tightly to Fc receptors on basophils and mast cells even before interacting with antigen. b) Involved in allergic reactions c) plays a role in parasitic helminth diseases

CLINICAL IMPLICATIONS OF HUMAN IMMUNOGLOBULIN CLASSES

IgG
1. Increases in:
a) Chronic granulomatous infections b) Infections of all types c) Hyperimmunization d) Liver disease e) Malnutrition (severe) f) Dysproteinemia g) Disease associated with hypersensitivity granulomas, dermatologic disorders, and IgG myeloma h) Rheumatoid arthritis

2. Decreases in:
a) Agammaglobulinemia b) Lymphoid aplasia c) Selective IgG, IgA deficiency d) IgA myeloma e) Bence Jones proteinemia f) Chronic lymphoblastic leukemia

CLINICAL IMPLICATIONS OF HUMAN IG CLASSES

IgM 2. Decreases in: 1. Increases (in adults) in: a) Waldenstrm's a) Agammaglobulinemia macroglobulinemia b) Lymphoproliferative disorders b) Trypanosomiasis (certain cases) c) Actinomycosis c) Lymphoid aplasia d) Carrin's disease (bartonellosis) d) IgG and IgA myeloma e) Malaria e) Dysgammaglobulinemia f) Infectious mononucleosis f) Chronic lymphoblastic leukemia g) Lupus erythematosus h) Rheumatoid arthritis

CLINICAL IMPLICATIONS OF HUMAN IMMUNOGLOBULIN CLASSES

IgA 1. Increases in:

2. Decreases in: a) Hereditary ataxia telangiectasia a) Wiskott-Aldrich syndrome b) Immunologic deficiency states (e.g., b) Cirrhosis of the liver (most cases) dysgammaglobulinemia, congenital c) Certain stages of collagen and and acquired agammaglobulinemia, other autoimmune disorders such as and hypogammaglobulinemia) rheumatoid arthritis and lupus c) Malabsorption syndromes erythematosus d) Lymphoid aplasia d) Chronic infections not based on e) IgG myeloma immunologic deficiencies f) Acute lymphoblastic leukemia e) IgA myeloma g) Chronic lymphoblastic leukemia

CLINICAL IMPLICATIONS OF HUMAN IMMUNOGLOBULIN CLASSES IgD 1. Increases in: a) Chronic infections b) IgD myelomas IgE 1. Increases in: a) Atopic skin diseases such as eczema b) Hay fever c) Asthma d) Anaphylactic shock e) IgE-myeloma 2. Decreases in: a) Congenital agammaglobulinemia b) Hypogammaglobulinemia due to faulty metabolism or synthesis of immunoglobulins

SUMMARY

Plasma contains many proteins with variety of function Albumin is the major CHON and is the principal

determinant of intravascular osmotic pressure Haptoglobulin binds extracorpuscular hemoglobin Transferrin binds iron, transporting it to sites where it is required Ceruloplasmin binds copper Immunoglobulins play a key role in the immune defense