HBV Surface Markers

Ok, so I felt like my last post (on HBIg) was fairly unclear regarding the markers of hepatitis B infection. Hopefully this clears things up.

 

The basis of hepatitis B infection (HBV) is the hepatitis B surface antigen (HBsAg). It is immunogenic, but not infectious. HBsAg is the protein in the viral envelope, and antibodies to surface antigen is what is measured for in a simple HBV test.

 

Ongoing HBV viral replication is indicated by the presence of serologic markers of the virion core. The virion core is composed of HBeAg and HBcAg. HBeAg is consistent with ongoing viral synthesis, and is generally found in areas with high viral endemicity. Strangely, when antibodies to HBeAg are present (Anti-HBe) this indicates relatively low infectivity in the individual, and may be a marker of the integrated stage of infection (Dienstag 2008).

 

HBcAg (Anti-HBc) is indicative of ongoing, chronic liver disease.

 

Lower titers of IGg anti-HBc with anti-HBs, show that infection with HBV had occurred in the past. High titers of IGg anti-HBc with low levels of anti-HBs show that viral infection has occurred, and is still present (Sherlock 1990).

 

 

References Cited

 

Dienstag, Jules L.

2008            Hepatitis B Virus Infection. New England Journal of Medicine 359(14):1486-1503.

Sherlock, S.

            1990            Hepatitis B: The Disease. Vaccine 8(Supplement):S6-S10.

 

Reactive Arthritis

Reactive arthritis (ReA) is a non‑purulent joint inflammation that usually follows bacterial gastrointenstinal or urogenital infections. The classic presentation of ReA is characterized by an asymmetric arthritis usually in the lower limbs associated with urethritis, conjunctivitis and occurrence of other articular or extra‑articular manifestations. ReA is classified as a type of seronegative spondyloarthopathy.
ReA not only affects the joints, but is also a systemic disease with extra‑articular symptoms. The clinical picture is dominated by syndromes of enthesitis (enthesopaties), peripheral arthritis (acute or subacute oligoarthritis mainly of the lower limb joints), pelvic and axial syndromes (spinal involvement with sacroilitis) and extramusculoskeletal syndromes.

Approximately 65–85% of patients with ReA are HLA‑B27 positive. Regardless of the preceding infection, the clinical picture is similar, but management can differ according to the triggering infection. Treatment of Chlamydia‑induced ReA should be started with antibiotics because of several mechanisms by which Chlamydia can cause persistent infection. The disease may have an acute or self‑limited course, however some patients develop chronic arthritis.

Etiology and pathophysiology of Reactive Arthritis:
Several factors contribute to the development of ReA, including:
1- The presence of bacteria or bacterial products in the joint and the local immune response directed against these bacteria
2- The effect of the arthritogenic peptides derived from ReA – triggering bacteria (Salmonella and Yersinia), which epitopes are presented by phagocytes to cytotoxic T lymphocytes in synovial membrane
3- Recognition of bacterial antigens outside
the cells, and forming complexes with class I human leukocyte antigens (HLA) and class II histocompatibility antigen (MHC II) presented on CD4 + and CD8 + T cells in Chlamydia infection
4- Tendency to persistent bacterial infections
and imbalance between tumor necrosis factor α (TNF‑α), interferon‑γ, IL‑12, IL‑10 activity (increased IL‑10 levels in the intestines, urogenital and respiratory system in patients with persistent infections).
5-Genetic factors also play an important role
in the etiology of ReA. The HLA‑B27 antigen is found in 65–80% of patients with ReA.

Extra‑articular manifestations of Reactive Arthritis:

Enthesopatic syndrome:
Heel pain, Achilles tendonitis, pain at the tibial tubercle
Pelvic and axial syndrome:
Sacroiliitis, spondylitis
Eye:
Conjunctivitis, iritis, keratitis, episcleritis
Genitourinary:
Urethritis, prostatitis, hemorrhagic cystitis, cervicitis
Gastrointestinal:
Diarrhea
Skin:
Keratoderma blennorhagica, circinate balanitis, oral ulcers, hyperkeratotis nails, erythema nodosum
Cardiovascular system:
Aortic disease, EKG conduction abnormalities
Renal:
Proteinuria, microhematuria, aseptic pyuria

Investigation of Progressive Inflammatory Neuropathy among Swine Slaughterhouse Workers – Minnesota, 2007—2008

This article appeared in MMWR on Feb. 8, 2008.

The Minnesota Department of Health conducted an investigation to characterize the outbreak of unexplained neurologic illnesses among workers in a swine slaughterhouse in southeast Minnesota. As of January 28.2008 12 workers at this plant had been identified with progressive inflammatory neuropathy (PIN). Median age of the 12 workers was 31years, and six patients were female. All 12 patients that had PIN reported being healthy before the onset of neurologic symptoms.

The symptoms of PIN reported by workers ranged from acute paralysis to gradually progressive symmetric weakness over periods ranging from 8 to 213 days. Eleven patients had evidence of axonal or demyelinating peripheral neuropathy by electrodiagnostic testing. A sample of cerebrospinal fluid was obtained from seven patients, and they all showed elevated protein levels with no or minimal pleocytosis. Five of these patients had evidence of inflammation on a spinal MRI (4 patients in peripheral nerves or roots and one patient in the anterior spinal cord).

All 12 patients with PIN reported either working at or having regular contact with an area known as the warm room where swine heads were processed (head table). Thus, a case-control study was conducted among the plant’s workers to identify the specific risk factors associated with neurologic illness. Ten patients out of the 12 initial reports of PIN were chosen that had confirmed or probable PIN. Also two stratified control groups were formed: 1) a random selection of 48 healthy warm-room workers and 2) all 65 healthy head-table workers. Blood samples and throat swabs were collected from all consenting case patients and controls. As of Jan 30, 2008 the lab investigations had not identified any infectious agent from the blood and throat swab specimens that would explain the occurrence of PIN.

The results of the case-control study highlighted several important aspects that could contribute to PIN among the workers. Seven of the ten case-patients were significantly more likely to have worked at the head table than warm-room controls (12 of 48). Also, case-patients were more likely to have removed brains or remaining skeletal muscle from the pig head (4 of 7) than head-table controls (8 of 65). Importantly, the illness was not determined to be related to previous travel outside or within the US, nor related to exposure to chemicals, fertilizers, insecticides, or use of medications and receipt of previous vaccinations.

An environmental assessment of the plant was conducted the better understand the methods of processing as well as the personal protective gear used by the workers. The investigators found that a compressed air device was used in the plant to harvest brain tissue from pig heads at the head table. The compressed air disrupted the brain material into a liquefied form that made it easier to remove the brain. However, this technique caused splatter possibly including aerosolized brain material to which the workers operating the device and other nearby might have been exposed. In response to this investigation, the plant suspended harvesting of brains and instituted additional protective gear that included face shields and long sleeves.

To date, three plants in the US used compressed air to remove pig brains including one in Nebraska and one in Indiana. Nebraska plant did not have reports of Pin, but the Indiana plant had similar histories of PIN as in Minnesota for workers exposed to head processing activities at that slaughterhouse. As a result of this, all three plants have stopped using compressed air devices for brain removal.

The FDA inspected the pigs processed by these plants and no food risk was identified for the general population. This investigation in Minnesota suggests that in the process of using the compressed air device, workers might have been exposed to aerosolized brain material through inhalation or contact with mucous membranes. The current hypothesis for development of PIN in the swine plant is that worker exposure to the aerosolized pig neural protein might have induced an autoimmune-mediated peripheral neuropathy. Thus, is it just a cross-reaction in the immune system caused by the similarity of the pig neural proteins to human proteins?

Using rare codon pairs to attenuate viruses.

A friend of mine who works at the CDC turned me on to a new technique they're working on to construct safe attenuated viruses to use as vaccines: Genome wide changes in codon pair bias.

A quick review of codons: each of the twenty amino acids is encoded by at least one 3 letter codon in RNA: for example, GCC is translated by ribosomes into an Alanine. Because there are 4 nucleotides availible, there are 4^3, or 64 possible 3 letter codons. Since only 21 (20 AA + a stop codon) are actually required, many amino acids are encoded by multiple sets of codons (eg. UCU, UCA, UCG, and UCC all encode Serine) The human genome, however, preferentially uses certian codons (GCC is four times as prevelent as GCG, though both encode Ala), and pairs of codons (GCAGAG and GCCGAA encode the same two amino acids, but the former is 7 times as prevelent in the human genome). As it turns out, our cellular machinery is tuned to translate common codon pairs more effecitvely than rare codon pairs.

A group of researchers has developed a way to build long DNA sequences, and with those sequences, generate poliovirus de novo, without any template. Using this technique, they were able to develop equivalent versions of poliovirus with identical protiens, but encoded with a varying degree of rare codons and rare codon pairs.

Because our cellular machinery translates rare codons poorly, a very large number of rare codons renders the virus totally ineffective at infection - creating no immune response. By including some rare codons, but some standard codons, the researchers were able to create a virus that is effective enough to trigger an immune response (and subsequent immunity - remember, the virus has identical protiens), but weak enough to prevent a true viral infection - an effectively attenuated virus.

As you may remember, some current live, attenuated vaccines have the possibility of reverting to virulence: for example, the oral polio vaccine, which has only 5 attenuating mutations, can, on rare occasions, revert to a virulent form - which is why it is no longer available on the US market. A rare codon virus, on the other hand, has hundreds of mutations, each contributing, in a small way, towards attenuating the virus; this leaves no chance of the virus reverting to virulence. This technique also allows for the systematic weakening of a virus - potentially allowing vaccine developers to precisely adjust the strength of an attenuated virus to maximize immunogenic effectiveness.

Reference:
J. Robert Coleman, Dimitris Papamichail, Steven Skiena, Bruce Futcher, Eckard Wimmer, and Steffen Mueller
Science 27 June 2008 320: 1784-1787 [DOI: 10.1126/science.1155761] (in Reports)

Smoking, Sugar Uptake, and Their Roles in Crohn’s Disease...

Smoking is a risk factor and a contributor to many diseases. Scientists have discovered that smoking tends to worsen the effects of Crohn’s disease. The aetiology and pathogenesis of Crohn’s disease, however, is still unknown. The mechanism of the effect of smoking on the colon is also unknown. Pathogens might cause some changes in bowel motility and susceptibility but it is hard to predict the mechanism of those changes. Moreover, smoking may produce complex changes in immune function including reduced natural killer cell activity in peripheral blood leukocytes and decreased immunoglobulin concentration in the serum and saliva.


Furthermore, some studies have shown that patients with Crohn’s disease consume more refined sugar than normal healthy people. Other studies revealed that people with Crohn’s disease who consume more sugar in their diet show exacerbated symptoms compared to those who consume less sugar. Since nobody knows how sugar injures the intestine, doctors recommend their patients to eliminate sugar from their diet, or change their diet from a high-carbohydrate to a low-carbohydrate.


Now, we know that sugar and smoking are bad for patients with Crohn’s disease. The challenging question is what will happen if a patient with Crohn’s disease has a combination of both risk factors? Some studies showed that sugar intake and smoking were independent risk factors for Crohn’s disease, but a combined exposure did not result in a further increase of the risk. Some researchers think that these factors might operate through a common mechanism. I did my research trying to get an answer but i found nothing. I believe those people who figured out that there is no increase in risk if you combine both factors should work hard to figure out the mechanism behind this.

Hepatitis B Immunoglobulin

Immunocompetent patients who are already positive for hepatitis B (HBV) are treated with INF-µ. Patients who have had a recent exposure should immediately be treated with hepatitis B immunoglobulin (HBIg). Interestingly, HBIg may have a variety of other applications for HBV infected patients. For example, it can be  administered to infants born to HBV positive mothers within 24 hours of birth to prevent neonate infection.

 

Perhaps the most interesting application, is that of the case of post-transplant patients. Immunosuppressed transplant patients may be treated with INF-µ2b to prevent allograft re infection. However, if allograft reinfection does occur, INF-µ2b can cause rejection, as was the case in a 1997 clinical trial of the drug. Discouragingly, if patients who are transplanted for chronic active infections do not receive any kind of post-transplant antiviral therapy, average estimated survival times range from only 1 – 5 years.

 

Treatment with HBIg in immunosuppressed post-transplant patients has been remarkably successful. HBIg has been shown to prevent allograft reinfection by maintaining anti-HBs titers at a level >250IU/L. This is so successful that it even prevents reinfection in patients with actively replicating viral infections!

 

Though this treatment is extremely effective, it is also expensive. For the first year of HBIg treatment, patients may be looking at a cost around $38,000! For every year after that, patients can expect to pay around $15,000 annually.  It seems extremely unfair that such effective treatment is reserved only for those who are able to afford it…

Got IBD? Sit under the Bodhi tree.

There is an intimate connection between the immune system and the nervous system. This makes sense because both play a role in systemic homeostasis. For example inflammation can be triggered by CNS stimulation. An electro-chemical signal starts in the CNS and is propagated into the periphery through sensory C-fibers. These nerves release substance P which cause the release of histamine from mast cells. Chemicals, physical touch, and emotional stress can all trigger the release of substance P. Beyond the hormonal connection there may be a direct synaptic connection. There is evidence of a Neuro-Immune synapse. These NI synapses are between axon terminals and immunocompetent cells such as mast cells, T-cells, and macrophages. These synapses are still under investigation but they appear to participate in cross talk between the nervous system and the immune system. So if your stress’n out find a quiet place and get your zen on, your body will appreciate it.
-Randy
P.S. Below is a pretty cool article if your into that sort of thing.

Citation:
Nakanishi M, FurunoT. Molecular basis of neuroimmune interaction in an in
vitro coculture approach. Cell Mol Immunol. 2008Aug;5(4):249-59.