Paget’s Diseases of Bone

Paget's disease is a disease of increased but uncontrolled bone turnover. It is thought to be primarily a disorder of osteoclasts, with excessive osteoclastic resorption followed by increased osteoblastic activity. Paget's disease is common (UK prevalence 5%) but symptomatic in only 1 in 20 patients

Predisposing factors

     §  Increasing age

     §  Male sex

     §  Northern latitude

     §  Family history

Clinical features - only 5% of patients are symptomatic

·         Bone pain (e.g. Pelvis, lumbar spine, femur)

·         Classical, untreated features: bowing of tibia, bossing of skull

·         Raised alkaline phosphatase (alp) - calcium* and phosphate are typically normal

·         Skull x-ray: thickened vault, osteoporosis circumscripta

Indications for treatment include bone pain, skull or long bone deformity, fracture, periarticular Paget's

·         Bisphosphonate (either oral risedronate or iv zoledronate)

·         Calcitonin is less commonly used now Complications

·         Deafness (cranial nerve entrapment)

·         Bone sarcoma (1% if affected for > 10 years)

·         Fractures

·         Skull thickening

·         High-output cardiac failure

Usually normal in this condition but hypercalcaemia may occur with prolonged immobilisation Paget's disease - old man, bone pain, raised ALP. The normal calcium and phosphate combined with a raised alkaline phosphate points to a diagnosis of Paget's

Acute Phase Proteins

The acute phase response is a quickly mobilized non-specific defensive response elicited in the response of the host to infection, tissue injury or inflammation.

Acute phase proteins 

Acute phase proteins have been defined as the proteins whose plasma concentration increases (positive acute phase proteins) or decreases (negative acute phase proteins) during the acute phase responses.

Acute phase proteins: Composition and Resource

APs are synthesized mainly by hepatic cells, the monocytes, and fibroblasts.

Acute phase proteins: Main Functions

1. To help the immune system adapt to various environmental stresses. removal of exogenous substance and necrotic tissue to promote the healing .for example：c-reactive protein c-reactive protein ＋ combine with bacterial wall activate complement classic pathway promote phagocytosis induce the expression of inflammatory cytokines and tissue factor in monocytes.

2. Inhibit the activity of protease: The protease inhibitors can protect tissues from over injuries by protease 

3. up-regulation of fibrinogen in the acute phase response is beneficial  to increasing the hemostatic power and the wound healing

4. ceruloplasmin, haptoglobin, and hemopexin can bind copper and heme, and avoid the injuries of tissues by over many copper and iron. Ceruloplasmin exhibits an antioxidant function against oxidative stress injuries.

5. serum amyloid protein A associated HDL3 seems to facilitate the uptake and removal of cholesterol from monocytes/macrophages at the inflammatory site

The structure and functions of BCR Complex

It’s a membrane Ig (IgM), associated glycoporotein, Ig α and Igβ , which has a moderately large cytoplasmic domain. These domains each include a short region important for transmitting a signal indicating antigen has bound. This region is called immune tyrosin based activation motif ( ITAM ).

Functions of BCR complex

On activation by antigen, B cells differentiate into plasma cells producing antibody molecules of the same antigen specificity as the receptors.

Organization of Immunoglobulins

Molecular Structure of Immunoglobulins

Immunoglobulins are enormous families of related but non-identical glycoproteins. It has been estimated that every human being is capable of producing at least 10⁸ different antibody molecules.

The Four-Chain Basic Unit

Immunoglubulin molecule is made up of two different types of polypeptides. The larger, heavy (H) chains are roughly twice as large as smaller, light (L) chain. Every immunoglobulin contains equal number of heavy and light chain poly peptides. The heavy and light polypeptide chains are both composed of folded globular domains, each of which is 100-110 amino acids long ad contains a single intra chain disulfide bond.

Immunoglobulin Variable Regions and Constant Regions

All the light chains and all the heavy chains in any single immunoglobulin protein are identical. However when compared with different immunoglobulins, there is a wide variation in sequences of the chain. This variation is mostly occurred in N-terminal domain, where as the sequences of other domain remain constant. Therefore N-terminal domain in heavy or light chain poly peptide is referred as variable region.

Hinge Region  

A short additional segment of amino acid located between the C_H1 and C_H2 domains of H chain is called hinge region. It is made up of predominant of cysteine and proline residues. The hinge region permits flexibility between the two Fab arms of the Y-shaped antibody molecule.

Hypervariable Region

Consists of relatively invariant stenches of 15-30 amino acids, separated by shorter region of extreme variability called hypervariable region that are each 9-12 amino acids long. Hypervariable regions are also called complementarity-determining regions.

J Chain and Secretary Components

J Chain

The secreted form of IgM and IgA generally exist as polymers of the basic four-chain unit that include a single additional polypeptide called the J chain.

The Secretary Components

Secretary component is a single glycopeptide with a peptide molecular weight of approximately 70,000 and a high carbohydrate content. The function of secretary component is to facilitate the trasepithelial passage of IgA.

Fundamentals of Complement System – Part 1

What is a Complement System?

Complement system consists of series of proteins which complement or augment the function of the antibodies and augment the inflammatory reactions.

Where the Complementary proteins are produced?

Complement proteins are produced by the liver or the hepatocytes, some of the complement proteins are produced in GI mucosa. There are more 20 proteins among the complement proteins. They can be defined as inactive proteins or inactive enzymes, which are activated only during inflammatory reaction and immune mediated reactions.

How Complement System is activated?

As soon as antibody (specially IGG and IGM)) bind with antigen it undergoes transformational changes and exposes a special domain which binds and activate the complement system.

Early stage of Complement System

Class of antibody (IGG or IGM ) binds with the antigen which activate complement protein number 1, once it is activated it hydraulically  breaks down the complement number 2 and 4. Complement number 4 is break down into ‘A’ and ‘B’ and similar break down happens to the complement number 2, ‘A’ and ‘B’ remain with the bold chain and complements move away. These similar sequences happen to the complement number C3 and make C5 converters, which has power to break down C5 and convert into active form.

Late events in Complement System

C5b complex with C5, C6, C7, C8 and C9 make a pentameric pore. This pore acts as a membrane attacking pore and destroy the physical integrity of bacterial lipid membrane. This membrane attacking complex is formed as a result of late events occurred in terminal pathway in complement system. The whole pathway, activation of the complement system is called classical pathway.

The Role C3b in Complement System 

C3b facilitates the phagocytosi of bacteria. Any molecule which facilitate the phagocytosis is called opsonin. The two know opsonin molecules are C3b and IGG