Scientists have found a missing puzzle piece in the mystery of leprosy

The missing piece of the puzzle

When was the last time you did a jigsaw? Sometimes you get stuck and you can’t find any pieces that connect, but then you find a piece that suddenly allows all the other pieces to slot into place. This is a process that Professor Dr Annemieke Geluk and her team at the Leiden University Medical Centre (LUMC) are currently going through with TLM's team in Bangladesh and Nepal through the ‘2B or not 2B’ project. Thanks to a discovery they have made, we may have found a new piece of the leprosy puzzle.

As Professor Geluk says, leprosy is an ancient disease because we have evidence of leprosy from at least 4,000 years ago, but it is also very much a contemporary disease, with so many medical mysteries unsolved. Thanks to this latest discovery, we are a step closer to a real understanding.

Do textbooks need to change?

The leprosy textbooks teach us that MB patients (those with a large amount of leprosy bacteria in their body) are different from PB patients (those with a low, sometimes undetectable bacterial load) because their immune system is not capable of killing the leprosy bacteria, whereas a PB patient's immune cells can. However, leprosy immunology is not as black and white as that. In the jigsaw puzzle of leprosy, this has turned out to be a piece stuck down in the wrong place, a misunderstanding that has been holding us back.

Professor Geluk and her team, with outstanding efforts by Dr Anouk van Hooij, have discovered that MB patients are capable of killing leprosy bacteria, whereas the opposite can be found for PB patients. Thus, the high bacterial load in MB patients is due to another immunological reason, namely the presence of B-cells that occur in both MB and PB patients who are able to control the growth of leprosy bacteria. These B-cells could very well play a key role in developing or not developing disease.

Want to know what a B-cell is? Here's how ChatGPT explains it

B-cells (short for B lymphocytes) are a type of white blood cells that help protect your body from infections.

In simple terms:

🛡️ They make antibodies – proteins that recognise and stick to germs like bacteria and viruses.
🎯 They’re very specific – each B-cell is trained to recognise one particular germ.
🧠 They remember infections – some B-cells become memory cells, so your body can fight the same germ faster next time.

How they work (quick version):

A germ enters your body.
A matching B-cell recognises it.
The B-cell multiplies and turns into a plasma cell.
Plasma cells release antibodies that help destroy the germ.

What will change because of this finding and the LUMC immunodiagnostics?

B-cells are constantly interacting with other cells, proteins, and bacteria in the body. When they do this, they produce molecules which can be measured directly in blood. Professor Geluk and her team are working on identifying proteins that are specifically secreted by these B-cells. Such proteins can become ‘flags’ that allow us to identify persons who can or cannot control bacterial growth.

In previous research, Professor Geluk’s team has identified other ‘flags’ that represent different pieces of the leprosy diagnosis puzzle. If the B-cell flags are identified, they can be combined with the other ‘flags’ and applied to a low-complexity rapid test (a fingerstick blood test) on an immunodiagnostic platform previously developed at the LUMC. This type of immunodiagnostic test, which can measure multiple ‘flags' in a person’s body, can be used by health care workers without much training, even in low-resource settings.

Diagnosis
As an adjunct tool for diagnosis of MB and PB, it can help decide whether a person has leprosy, and also which type, allowing us to provide the right MDT prescription.

Treatment
It could tell us if a patient is responding to treatment. If they are not, it could mean other treatment options should be looked into or whether patients are not taking antibiotics. Also, the efficiency of new drugs for leprosy could be monitored during treatment and compared to current regimens.

Evaluating PEP regimens
Several regimens of PEP are being evaluated worldwide. Using an immunodiagnostic test for both direct and long-term effects on infection of a PEP regimen will show us whether PEP is working efficiently.

Predicting reactions
The most important cause of leprosy-induced nerve damage are reactions that mostly occur during treatment. If patients are monitored with immunodiagnostic tests, this can help early detection of reactions or even predict them.

What are the next pieces of the puzzle?

Now that we discovered these specific B-cells, we will combine these with other pieces of the leprosy puzzle so it will start to fit into place. Professor Geluk puts it like this:

"Since there are many aspects we still don't know exactly about how exposure to leprosy bacteria leads to disease, identification of proper markers of protection or disease will help diagnose patients earlier. The reality is, we are unlikely to eliminate leprosy while these issues remain unsolved.

"Second, although this is an ancient disease, we are now applying modern technologies to solve the puzzle. With claims of elimination on one hand and major technological advancement on the other, this is a perfect time to invest in leprosy reserach.”

Photo credit: Ruth Towell

Another Leiden-Bangladesh Collaboration: Measuring where transmission is still ongoing below the radar

A “flag” for infection with M.leprae that has been studied since the 1980s is represented by antibodies against phenolic glycolipid-I (PGL-I), a molecule unique to leprosy bacteria, constituting large parts of their outside. These antibodies correlate well with bacterial load but cannot distinguish between past and recent infections. However, in young children, infection is recent by definition.

Fifteen years ago, the LUMC team developed a rapid test that not only can detect these antibodies (like a Covid test) but can also measure their levels in blood (doi: 10.1016/j.clinbiochem).

In an extensive literature study, Louise Pierneef, a PhD student in Professor Geluk’s group, showed that large studies using quantitative analysis of these antibodies in healthy young children were seriously lacking. Subsequently, the LUMC-team started the first serosurvey in healthy young children in Bihar, India in 2020 and showed the test was well accepted both by healthcare workers and the population. Based on the above, the WHO Task Force on definitions, criteria and indicators for interruption of transmission and elimination of leprosy (TFCEL) recommended to consider using anti-PGL-I seroprevalence in young children as a criterium for monitoring (interruption of) transmission in the whole population.

In 2023, the Professor Geluk's team continued with child serosurveys in Makassar and Sumba (Indonesia), which was extended with a large scale serosurvey in Papua by one of Professor Geluk’s PhD students, Hana Krismawati.

Comparison of transmission levels by seroprevalence in healthy young children, before and several years after a population intervention such as PEP, provides information on the efficiency of this intervention (see the ‘missing piece’ article).

As several types of PEP were on the verge of being studied or had just been performed in Bangladesh, LUMC and TLMB joined forces and a child serosurvey was initiated in northwest Bangladesh to determine baseline transmission. With enormous efforts of the TLMB team 6,000 young children were sampled, painting an invaluable picture of transmission in Bangladesh.