DIPHTHERIA

DIPHTHERIA-

• it is caused by gram (+)ve corynebacterium diphtheria. Naturally, it is pathogenic only to humans. It colonizes the nasopharyngel  tract and lives in the superficial layers of respiratory mucosa.
• it is spread between humans by respiratory droplets.
• There is little tissue damage and mild inflammatory reactions due to growth of the organism. It's virulence is mainly due to it's exotoxin.
• The toxin causes destruction of the underlying tissue and this results in the formation of a tough fibrous membrane  comprised of WBC, fibrin and dead epithelial cells of the respiratory  system.
• This membrane is very suffocating.

Besides,exotoxin is also responsible for systemic manifestations like ;
1)myocardial damage which results in congestive heart failure; and
2)neurologic damage resulting in muscle weakness or paralysis.

The exotoxin is encoded by Tox gene of phage B; so only those strains that carry the lysogenic phage beta are able to produce toxin.

The toxin consists of :
1)A binding chain
2)A toxin chain

• The binding chain helps the bacteria to bind to the ganglioside receptors present on the host cell and thus in internalization of exotoxin.
• Toxicity results from inhibitory effect of the toxin chain on protein synthesis.
• 
  
• The diptheria toxin is very potent as only it's single molecule can kill the cell.

Diptheria toxoid:

• The diptheria toxoid is prepared by treating the toxin with formaldehyde. This binding leads to irreversible loss in the toxicity of toxin but it's antigenicity is retained.
• The toxoid is administered as DPT vaccine to 6-8 weeks old kids. Immunizations with toxoid results in the production of anti-toxin.
• Because, anti-toxin levels decline slowly overtime. So,booster doses are given every 10 years to maintain antitoxin level within protective range.

TUBERCULOSIS :

• Although many mycobacterium species can cause tuberculosis ;but Mycobacterium Tuberculosis is the principal causative agent.
• It is spread thtough respiratory secretions.
• The inhaled bacteria gets in to alveoli of lungs; and are ingested by alveolar macrophages ;  in the macrophage,  they are able to survive and multiply intracellularly by inhibiting the formation of phagolysosome.
• When the infected macrophage lyse; then large number of  bacilli are released. This leads to activation of CD4+ cells and a large number of macrophages are infiltrated to the site of infection.
• The activated macrophages wall off the organism inside a granulomatous lesion called tubercle.

Role of cytokines :

• CD4+ T cells produce cytokines such as IL-12 and IFN-gamma. IL-12 stimulate the production of T-helper  (1) cells and also induces the production of chemokines to attract macrophages to the site of infection.  When IL-12 is blocked by anti-IL12; then granuloma formation is blocked. Similarly,  mice vaccinated with BCG vacvine dies when IFN-gamma was not present and survived in it's presence.

Treatment :

• Tuberculosis is treated using several drugs in combination like rifampin,streptomysin,iisoniazid etc.
• The combination therapy of rifampin and isoniazid has been very effective. But, the intracellular growth of the bacteria make it difficult for the drug to reach them. And so, drug therapy must be continued for atleast 9 months to eliminate the bacteria.
• DOT ensures compliance with the lengthy drug regimen.
• Only vacvine for tuberculosis is an attenuated strain of M.bovis called BCG (bacilli calmette guerin). The vaccine has proved effective agaun8chtonic pulmonary tuberculosis;  but has been consistent against pulmonary tuberculosis.
• In different studies ,BCG has been gound to be 0 to 80% effective in the vaccinated individuals. In many cases, it has even increased the risk of infection.

BIOLOGY NOTES: IMMUNITY AND INFECTIONS :BACTERIAL

BIOLOGY NOTES: IMMUNITY AND INFECTIONS :BACTERIAL: INTRODUCTION As we know, bacteria enter our body through a number of routes or through breach in our skin or mucous membrane.  But, i...

IMMUNITY AND INFECTIONS :BACTERIAL

INTRODUCTION

• As we know, bacteria enter our body through a number of routes or through breach in our skin or mucous membrane. 
• But, it's ability to cause a disease and the immune response generated by the host depends very much on the inoculum size and it's virulence.
• If the inoculum size and the virulence both are low; then innate immunity comes in to play.
• On the other hand, if the inoculum and virulence both are high then adaptive response is generated.
• Immune response also depends on whether it's an extracellular or intracellular bacteria.

Immune response against extracellular bacteria :

Extracellular bacteria are pathogenic for 2 reasons:
1)They induce a localised inflammatory response.
2)They produce toxins.And, these toxins can be cytotoxic or cause pathogenesis in other ways.e.g. Diphtheria toxin blocks the protein synthesis.

In response to these bacteria,  antibodies are secreted which can work in various ways to tackle the bacteria.

• Antibodies may bind to antigens  on the bacterium and activate complement system.After this, the bacteria can be lysed or opsonized for phagocytosis.
• Antibody -activated complement can also lead to release of anaphylotoxins and chemotactic factors which further help in phagocytosis.
• Besides,antibody can bind to toxins to form antibody-toxin complex which is cleared by phagocytosis  just as Ag-Ab complex.

Immune response against Intracellular bacteria :

• Innate immunity is not effective in this case ,although NK cells provide an early defense against these bacteria.
• CMI is the main response against Intracellular bacteria and among them too, more specifically DTH response acts. In this response, cytokines secreted by  CD4+ T cells are important; notably IFN-gamma , which activates macrophages to kill ingested pathogens more effectively.

EVASION OF THE HOST RESPONSE BY BACTERIA
There are 4 steps in bacterial infection :
1) Attachment to host cell,
2) Proliferation,
3) Invasion of host tissue,
4) Toxin induced damage to host cells.
Host defense mechanisms act at each of these steps  and many bacteria have evolved ways to circumvent some of them.
Attachment to the host cell:
Some bacteria have surface structures or molecules that enhance their ability to attach to host cells.e.g.
1) A number of gram negative bacteria have pili which enable them to attach to the membrane of the intestinal or genitourinary tract.
2) Others sub as bordetella secrete adhesion molecules which attach to both the bacterial and host cell .

Host defense mechanisms : 

• secretory IgA molecules are the main host defense against bacterial attachment to the mucosal epithelial cells. But many bacteria have developed strategies to tackle this.
• E.g. Neisseria gonorrhoeae , hemophilus influenza, and neisseria meningitidis secrete protease which cleave IgA molecule at the hinge region and make it malfunctioning.
• Neisseria gonorrhoeae evade the immune response also by changing their surface antigens preferably pilin sequence ).

Proliferation :
Host defense mechanisms :
1) phagocytosis 
2)complement mediated lysis and localised inflammatory response.

a) phagocytosis -

• host tries to handle the microbe through phagocytosis;  but some bacteria possess surface structures to inhibit phagocytosis.
• Polysachharide capsule of S.pneumonia, M protein of S.pyogens and the ability of some staphylococcal bacteria to assemble a fibrin coat around them help to escape phagocytosis.

b)complement mediated lysis and localized inflammatory response :

• Mechanisms to interfere  with the complement system help bacteria survive.
• E.g. long side chains on the lipid A moiety of the cell wall  polysaccharide help to resist lysis  in gram (-)ve bacteria.
• Some gram (+)ve bacteria show a generalized resistance to complement mediated lysis.

Invasion of host tissues:

• Host tackle this by Ab-mediated agglutination. e.g. pseudomonads  secretes an enzyme elastase that inactivates both the C3a and C5a anaphylotoxins that diminish the localized inflammatory reaction.

Toxin induced damage to host cells:

• Host tackle this through neutralisation of toxin by antibody. But, bacteria secrete hyaluronidase that enhance bacterial infections .

NOTE:

• A lot of bacteria even has the Ability to survive within phagocytic cells:.e.g.Listeria monocytogens survive with in  phagocytic  cells by escaping from the phagolysosome in the cytoplasm which provides a favorable environment for growth.
• Mycobacterium avium block formation of phagolysosome  and some mycobacteria are resistant to the oxidative attack that takes place within phagolysosome.

SOME COMMON BACTERIAL DISEASES:Diptheria and tuberculosis

BIOLOGY NOTES: (INFLUENZA) as an example of VIRAL INFECTIONS :imm...

BIOLOGY NOTES: (INFLUENZA) as an example of VIRAL INFECTIONS :imm...: This post is an extension to viral infections under immunity and infections.  Click here for the main content  http://biomaniac9.blogspot...

BIOLOGY NOTES: IMMUNITY AND INFECTIONS 1 : VIRAL

BIOLOGY NOTES: IMMUNITY AND INFECTIONS 1 : VIRAL: INTRODUCTION: To finally establish an infection, the pathogen has to deal with both innate and adaptive immunity. Our immune system reco...

(INFLUENZA) as an example of VIRAL INFECTIONS :immunity and infections

This post is an extension to viral infections under immunity and infections.  Click here for the main content http://biomaniac9.blogspot.com/2016/03/immunity-and-infections-1-viral.html

INFLUENZA (AN EXAMPLE):

Influenza infects the upper respiratory tract and major central airways in humans,horses,birds,pigs and even seals.

STRUCTURE

Envelope:

• They are spherical or ovoid and surrounded by an outer envelope which is a lipid bilayer acquired from the plasma membrane of the infected host.
• 2 types of glycoproteins are inserted into the envelope: hemagglutinin, neuraminidase
• Hemagglutinin: they are in the form of trimers and help virus to attach to the host cells.They are approx 1000 in numbers .
• Neuraminidase:They facilitate viral budding from the host cell by cleaving N-acetylneuraminic acid(sialic acid) present in nascent viral glycoproteins and host cell membrane glycoproteins.

Matrix protein:

It is present beneath the envelope and it surrounds the nucleocapsid.

Nucleocapsid:

The nucleocapsid consists of 8 different ssRNA which encodes protein and RNA polymerase. Each RNA strand encodes one or more different influenza proteins.

TYPES:
3 types of influenza viruses are there:
Type A-It is the most common type and responsible for the major human pandemics.
Type B- It causes human diseases but not animal diseases and has caused epidemics.

Type C-It causes mild human illness.

NOMENCLATURE:
As we know, antigenic variation gives rise to a number of subtypes of infulenza.
A/C to the nomenclature of WHO, each virus strain is defined by
1)The animal from which it was first isolated
2)The place from where it was isolated

3)Strain number
4)Year of isolation
5)Antigenic description of HA and NA.

e.g.A/Sw/Lowa/15/30(H1N1) designates strain A isolate 15 that arose in swine in lowa in 1930 and has antigenic subtypes 1 of H1 and N1.

NOTE:There are 13 different hemagglutinin and 9 neuraminidase spikes protruding from the viral envelope in case of type A influenza virus.
On the other hand, neither type B nor C is classified by H and N subtypes.

2 different mechanisms generate antigenic variability in HA and NA.
1)antigenic drift
2)antigenic shift

Antigenic drift:

• It involves a series of spontaneous point mutations that result in minor changes in HA and NA.

Antigenic shift:

• It involves sudden emergence of a new subtype of influenza whose HA and NA are different from that virus which was present in a preceding epidemic.It is thought to occur through genetic reassortment between influenza virions from humans and from various animals like pigs, horses, ducks.
• E.g.In a pig infected with human H3N2 and swine H1N1, H3N1 was recovered.
• Antigenic shift results in antigenic variation for which the immune system lacks memory and is unprepared. This results in outbreaks of influenza, sometimes reaching pandemic proportions.
• Among all these, virus undergoes Ag-drift generating minor variations, which account for strain differences within a subtype.
• An individual infected by a given strain mount an immune response against it so that the strain is eliminated. But, if too many point mutations are accumulated; then antigenicity is altered to an extent that they are able to escape immune elimination.
• These variants become a new strain of influenza; causing another local epidemic cycle.

Jumping viruses:

• Besides, a virus with even little genetic change can become capable of causing infections or epidemics in a new species.e.g. virus H3N8 caused infulenza epidemics in racing dog.This virus was 96 %identical to the virus known to have existed in horses for 30 years.

Humoural responses to influena:

• Antibody specific for the HA molecule is produced during an influenza infection.
• This antibody is strain-specific and protects against a given strain.
• The titers of these serum antibodies peak within few days of infection and then decrease over the next 6 months but then it plateaus and remain stable for several years.
• This Antibody is not needed to treat influenza but to protect against reinfection by the same strain.
• This is supported by the fact that patients with agammaglobulinemia  recover from the disease. And, experimentally it has been proved that if mice are infected with influenza virus and Ab production is experimentally suppressed; the mice, though, recover from the infection but can be reinfected with similar strain.

IMMUNITY AND INFECTIONS 1 : VIRAL

INTRODUCTION:

• To finally establish an infection, the pathogen has to deal with both innate and adaptive immunity.
• Our immune system recognize the pathogens as foreign with the help of antigens present on their surface.
• So, to evade the immunity, the pathogens initially try to escape the recognition by following the strategies as below:-

1. They grow inside the host cells so that they are sequestered from the immune attack.
2. They shade their membrane antigens to escape the recognition.
3. They camouflage by mimicking the surface of host cells so that they are not recognised as something foreign or different .
4. Some pathogens escape immune attacks by regulating the immune system and activating a branch of the immune system which is ineffective against them.
5. Many of them continually change their surface antigens, so that memory never works in their case.
6. Although vaccines and drugs have helped a lot to fight infections and even eliminate a few; but impaired immunity due to immunosuppressive drugs and infections from HIV has really worked to spread both rare and new diseases.

Based on the infections involved; there are:-

1)viral infections,

2)Bacterial infections,

3)Parasitic infections,

4)Fungal infections.

VIRAL INFECTIONS:

Introduction: viruses are segments of nucleic acids enclosed in a protein or lipoprotein coat.

typically, viruses preempts the biosynthetic machinery of the host to replicate it's own genome But, in many cases; the replication is error prone and generates numerous mutations.

Actually, from survival point of view, the virus is more likely to survive if it doesn't kill the host; but accumulating mutations give rise to strains which are harmful to the host and kill it.So now, virus requires to move to the new host .

virus is transmitted in the following ways:

1. The virus may become latent for a given period inside the host before death or illness; during which time the host may pass the virus to others.e.g.HIV
2. The virus can transmitt itself during even a short acute illness.e.g. influenza, small pox virus.
3. life cycle of viruses pathogenic for humans may also include nonhuman hosts. E.g. west nile virus. West Nile Virus replicates inside the birds and is carried by mosquitoes from the infected birds to humans or horses. They may also be passed between humans by blood transfusion and from infected pregnant mothers to their newborns.

Immune system against viruses:

INNATE IMMUNITY

• innate immune responses to viral infections primarily consist of interferons- alpha & beta and natural killer cells
• During it's life cycle, virus produces Ds RNA molecule which is detected by Toll-like receptors.This detection leads to expression  of IFN-alpha & beta by the infected cell.
• IFN-alpha and beta binds to their respective receptors and activates JAK-STAT pathway, which in turn induces the transcription of several genes.
• one of these genes encodes an enzyme known as 2'-5'-oligoadenylate synthetase which activates RNAse L that degrades viral RNA.
• other genes  inhibit viral replication.e.g. a specific protein kinase called dsRNA-dependent protein kinase (PKR) is induced which leads to inactivation of protein synthesis thus blocking viral replication in infected cells.
• Binding of IFN-alpha & beta to NK cells induces lytic activity ;making them very effective in killing virally infected cells.

ADAPTIVE IMMUNITY
Humoural immunity:(before virus attaches to host cells)

• Viruses have receptors which help them bind to molecules present on the surface of host cell.e.g. influenza virus binds to sialic residues of glycolipids or glycoproteins present on the host surface, EBV binds to type 2 complement  receptors on B cells.
• So, antibody again these receptors can be produced to block infection by preventing the binding of viral particles to the host cells.IgA in mucous secretions function in a similar way. The oral polio vaccine produces secretory IgA and block the attachment of poliovirus along the gastrointestinal tract.

Humoural immunity:(after virus attaches to the host cells)

• After virus attaches to the host cell, it tries to penetrate the host. 
• Antibodies can block the penetration by binding to epitopes which helps to mediate the fusion of the viral envelope with the host membrane.
• If the induced antibody is of complement activating type. Then, virus can be lysed or opsonized for phagocytosis to eliminate it.

Cell mediated immunity against viruses:

• Humoural immunity works in case of acute infections; but in case of latent state, CMI acts.
• Activated T-helper(1) cells produce a number of cytokines like IL_2,IFN-gamma, and TNF.
• In most viral infections; specific CTL activity arises in 3 to 4 days after infection, peaks by 7 to 10 days and then declines in later days.
• In initial days, IL-2 and IFN-gamma activate NK cells, which works to fight viruses until a specific CTL response develops; which then eliminates virus-infected self cells and thus eliminate potential sources of new virus.

EVASION OF HOST IMMUNE RESPONSES BY VIRUSES:
viruses follow the given strategies to evade immune response:
1)Encoding proteins
2)Targetting MHC
3)Evasion of complement mediated destruction
4)Change in antigens
5)Immunosuppression

1)Encoding proteins

• A number of viruses encode proteins that interfere with host defenses. e.g. hepatitis C virus blocks or inhibit the action of PKR which helps inhibit the viral replication.

2)Targetting MHC

• E.g. herpes simplex virus produce an early protein called ICP47.ICP47 inhibits TAP which is needed for antigen processing
• Adenovirus downregulate class 1 MHC expression.
• CMV and HIV downregulate class 2 MHC expression.

3)Evasion of complement mediated destruction:

• E.g. vaccinia virus secretes a protein that binds to the C4b and thus the classical component of complement pathway gets blocked.
• Herpes simplex virus has a glycoprotein component that binds to the C3b component and blocks both the classical and alternative pathway.

4)Change in antigens:

• A number of viruses work to change their surface antigens so that memory never works against them and our immunity fails to genuinely protect us.e.g.Influenza , HIV and rhinoviruses.

5)Immunosuppression:

• A number of viruses evade immune responses by causing generalized immunosuppression, which in turn, is caused by direct infection of lymphocytes or macrophages and lysing or breaking them; or by causing a cytokine imbalance.
• e.g. EBV produces a protein called BCRF1 that suppresses cytokine production by T-helper (1) cells resulting in decreased levels of IL-2, TNF and IFN-gamma.

Viral infections can be exemplified through INFLUENZA explained below.. http://biomaniac9.blogspot.com/2016/03/influenza-as-example-of-viral.html

BIOLOGY NOTES: COMPONENTS OF IMMUNE SYSTEM INVOLVED IN GRAFT REJE...

BIOLOGY NOTES: COMPONENTS OF IMMUNE SYSTEM INVOLVED IN GRAFT REJE...: COMPONENTS OF IMMUNE SYSTEM INVOLVED IN GRAFT REJECTION: Involvement of T cells- experimentally , it has been proved that lymphocytes ...

COMPONENTS OF IMMUNE SYSTEM INVOLVED IN GRAFT REJECTION:

COMPONENTS OF IMMUNE SYSTEM INVOLVED IN GRAFT REJECTION:

Involvement of T cells-

experimentally , it has been proved that lymphocytes could transfer allograft immunity but serum antibody couldn't. i.e. nude mice which lack a thymus and as a result functional T cells couldn't reject a graft. they even accepted xenografts..
Both CD4+ and CD8+ cells are involved; and experimentally; it was observed that :

       a) removal of only CD8+ had no effect on graft rejection,
       b) removal of only CD4+ cells lead to survival of graft for 15-30 days,
       c) removal of both CD4+ and CD8+ cells lead to survival of graft for upto 60 days.


Among T-helper cells; T helper (1) cells are major contributors.


Involvement of dendritic cells:

Dendritic cells act as APC and present exogenous antigens in context of MHC1 molecule to CD8+ or cytotoxic T cells; thus helping in the recognition of alloantigens as part of the rejection process.
so, inhibiting dendritic cells and thus interfering with the presentation of antigen can help graft acceptance.
besides, pretreatment with donor dendritic cells is also beneficial and has been shown to prolong the acceptance of both head and pancreas transplants in mouse experiments.


Involvement of MHC:

cells tissues that are similar in context of antigens they contain are called histocompatible and transplantation between  histocompatible tissues donot induce immune response whereas the one between histoincompatible tissues does.
Various antigens determining histocompatibility are encoded by more than 40 different loci but the most responsible loci are associated with MHC.
the main reasons for graft rejections are as below:

          a) difference in blood group of donor and acceptor,
          b) relation between major histocompatibility antigens,
          c) relation between minor histocompatibility loci.

TESTS OF COMPATIBILITY BETWEEN DONOR AND ACCEPTOR

Initially, the donor and recipient are tested for blood-group compatibility.
The blood group antigens are expressed on RBC, epithelial cells and endothelial cells.
Antibodies produced to anitgens present on graft induce antibody-mediated complement lysis of the incompatible donor cells.
MHC matching-Hla typing of donor and recipient is accomplished through;

          a) a microcytotoxicity test,
          b) mixed lymphocyte reaction(MLR)

Microcytotoxicity test-

WBC from donor and recipient are distributed into wells on a microtiter plate. Now, the antibodies for various MHC-1 and MHC-2 allele are added to these wells. Now the plate is incubated and complement is added to the wells.
Now, if antigen and antibody form complexes then addition of complement lyse them and the dead cells take up a dye such as trypan blue. This indicates the presence or absence of various MHC alleles and the one from donor and recipient can be matched.


Mixed Lymphocyte Reaction:

MLR is used to quantify the degree of class 2 MHC compatibility between the donor and the recipient.
lymphocytes from the donor is irradiated or treated with mitomycin C. It serves as antigen or stimulator cells and lymphocytes from recipient proliferate in response to this. Higher the proliferation, more is the difference between donor and recipient and poor is the probability of graft survival. This is measured by uptake of  tritium-thymidine into cellular DNA.It is advantageous because it gives an indication of t-helper cell activation in response to class 2 MHC antigen of the graft.
it is disadvantageous for the fact that, it takes several days to run the assay and in case, the donor is a cadavar, the organ should be used asap after it's removal from the cadavar and to wait for the results of the MLR assay becomes a problem.



Minor histocompatibility complex:

The major MHC molecules are recognized directly by helper and cytotoxic T cells by a phenomenon termed as alloreactivity.
In contrast, MHC(minor) antigens are recognized only when they are presented in the context of self-